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Khayal EES, Elhadidy MG, Alnasser SM, Morsy MM, Farag AI, El-Nagdy SA. Podocyte-related biomarkers' role in evaluating renal toxic effects of silver nanoparticles with the possible ameliorative role of resveratrol in adult male albino rats. Toxicol Rep 2025; 14:101882. [PMID: 39850515 PMCID: PMC11755029 DOI: 10.1016/j.toxrep.2024.101882] [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: 10/06/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 01/25/2025] Open
Abstract
Extensive uses of silver nanoparticles (Ag NPs) in different industries result in exposure to these nanoparticle imperatives in our daily lives. Resveratrol is found in many plants as a natural compound. The present study aimed to estimate the renal toxic effects of Ag NPs in adult male albino rats and the underlying relevant mechanisms while studying the possible role of resveratrol in ameliorating these effects. Thirty adult albino rats were split into 5 groups; control, vehicle, resveratrol (30 mg/kg), Ag NPs (300 mg/kg), and resveratrol + Ag NPs groups. The treatments were given orally for 4 weeks. Ag NPs group displayed a reduction in kidney weight ( absolute and relative), excess in urinary levels of kidney injury molecule, neutrophil gelatinase-associated lipocalin, cystatin, and blood kidney biomarkers (creatinine, urea, and potassium), increases in oxidative stress markers with the reduction in antioxidant markers, and decreases in serum sirtuin 1(SIRT1) level. Upregulation of interleukin 1 beta, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 gene expressions with downregulation of nephrin and podocin gene expressions in renal tissues were also observed. These changes were associated with histological alterations of the glomeruli and tubules, and increased area percentage of collagen fiber. A significant increase in the optical density of transforming growth factor-beta 1 and claudin-1 immunostaining was detected in the Ag NPs group when compared to other groups. All these changes were alleviated by the usage of resveratrol through its anti-oxidant, anti-inflammatory, and activation of SIRT1 recommending its use as a renoprotective agent.
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Affiliation(s)
- Eman El-Sayed Khayal
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Egypt
| | - Mona G. Elhadidy
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt
- Department of Medical Physiology, Faculty of Medicine, Al-Baha University, Saudi Arabia
| | - Sulaiman Mohammed Alnasser
- Department of Pharmacology and Toxicology,College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Manal Mohammad Morsy
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Egypt
| | - Azza I. Farag
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Egypt
| | - Samah A. El-Nagdy
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Egypt
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Maes L, Szabó A, Van Haevermaete J, Geurs I, Dewettinck K, Vandenbroucke RE, Van Vlierberghe S, Laukens D. Digital light processing of photo-crosslinkable gelatin to create biomimetic 3D constructs serving small intestinal tissue regeneration. BIOMATERIALS ADVANCES 2025; 171:214232. [PMID: 39983500 DOI: 10.1016/j.bioadv.2025.214232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 01/27/2025] [Accepted: 02/13/2025] [Indexed: 02/23/2025]
Abstract
Regeneration of small intestinal mucosal tissue could offer a promising strategy for Crohn's disease patients suffering from chronic inflammatory damage. Here, we aimed to develop hydrogels that mirror the villi and crypts of the small intestine and exhibit a physiological stiffness of G' ~ 1.52 kPa. For this purpose, we developed gelatin-methacryloyl-aminoethyl-methacrylate (gel-MA-AEMA)-, and gelatin-methacryloyl-norbornene (gel-MA-NB)-based biomaterial inks to fabricate 3D hydrogels ("villi only" versus "crypts and villi") with digital light processing (DLP) and co-cultured Caco-2/HT29-MTX cells. Gel-MA-AEMA was selected for its higher amount of methacrylates which was hypothesized to provide superior photo-crosslinking kinetics and hence superior DLP fabrication potential while gel-MA-NB was evaluated for its selective functionalization potential with thiolated bioactive compounds following DLP processing, resulting from its incorporated NB moieties which remain unreacted during the DLP process. Both gel-MA-AEMA-, and gel-MA-NB-based hydrogels exhibited a physiologically relevant stiffness, but only the gel-MA-AEMA-based biomaterial ink could be successfully utilized for printing hydrogels encompassing villi and crypts. Paracellular permeability of small sized marker molecules in combination with transepithelial electrical resistance measurements showed the formation of a functional barrier over time on all hydrogel constructs. Transmission electron microscopy and enterocyte differentiation marker genes' expression levels revealed the superior differentiation of Caco-2 on the 3D constructs compared to 2D hydrogel sheets. In summary, while both hydrogels enhanced functional barrier formation and enterocyte differentiation, gel-MA-AEMA proved more conducive to DLP compared to gel-MA-NB. Furthermore, our study underscored the benefits of cultivating intestinal cells on soft 3D constructs, enhancing cell barrier properties and differentiation, thus providing added value over traditional 2D supports.
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Affiliation(s)
- Laure Maes
- IBD Research Unit, Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium; Barriers in Inflammation Lab, Department of Biomedical Molecular Biology, Ghent University, Ghent 9000, Belgium; VIB-UGent Center for Inflammation Research, VIB, Ghent 9000, Belgium
| | - Anna Szabó
- Polymer Chemistry and Biomaterials Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Ghent 9000, Belgium
| | - Jens Van Haevermaete
- IBD Research Unit, Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium; Polymer Chemistry and Biomaterials Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Ghent 9000, Belgium
| | - Indi Geurs
- Food Structure & Function Research Group, Department of Food Technology, Safety and Health, Ghent University, Ghent 9000, Belgium
| | - Koen Dewettinck
- Food Structure & Function Research Group, Department of Food Technology, Safety and Health, Ghent University, Ghent 9000, Belgium
| | - Roosmarijn E Vandenbroucke
- Barriers in Inflammation Lab, Department of Biomedical Molecular Biology, Ghent University, Ghent 9000, Belgium; VIB-UGent Center for Inflammation Research, VIB, Ghent 9000, Belgium
| | - Sandra Van Vlierberghe
- Polymer Chemistry and Biomaterials Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Ghent 9000, Belgium.
| | - Debby Laukens
- IBD Research Unit, Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium.
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Yin Q, Zhang Y, Xie X, Hou M, Chen X, Ding J. Navigating the future of gastric cancer treatment: a review on the impact of antibody-drug conjugates. Cell Death Discov 2025; 11:144. [PMID: 40188055 PMCID: PMC11972320 DOI: 10.1038/s41420-025-02429-5] [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: 11/05/2024] [Revised: 03/07/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
Gastric cancer, marked by its high incidence and poor prognosis, demands the urgent development of novel and effective treatment strategies, especially for patients ineligible for surgery or those who have had limited success with chemotherapy, radiotherapy and targeted therapies. Recently, antibody-drug conjugates (ADCs) have become a key area of investigation due to their high specificity and potent antitumor effects. These therapies combine monoclonal antibodies, designed to bind to tumor-specific antigens, with cytotoxic agents that selectively target and destroy malignant cells. ADCs have generated significant interest in clinical trials as a promising approach to improve both treatment efficacy and patient outcomes in gastric cancer. However, their clinical application is not without challenges and limitations that must be addressed. This review discusses the recent progress in the use of ADCs for gastric cancer treatment.
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Affiliation(s)
- Qingling Yin
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Yanlong Zhang
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
| | - Xueqing Xie
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
| | - Meijun Hou
- Graduate School, Zunyi Medical University, Zunyi, Guizhou, 563006, China
| | - Xunsheng Chen
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guiyang, China
| | - Jie Ding
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guiyang, China.
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Klamminger GG, Bitterlich A, Nigdelis MP, Ertz M, Yoo-Jin K, Hasenburg A, Wagner M. Claudins in vulvar cancer - from epithelial barrier to potential tumor-agnostic cancer therapy. Tissue Barriers 2024:2444724. [PMID: 39722127 DOI: 10.1080/21688370.2024.2444724] [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: 12/10/2024] [Accepted: 12/15/2024] [Indexed: 12/28/2024] Open
Abstract
The immunohistochemical expression of various members of the claudin family has already been studied in pathological affections of the vulva whether to differentiate precancerous lesions from vulvar squamous cell carcinoma or in inflammatory conditions such as lichen sclerosus. From an oncological perspective, however, immunohistochemical analysis of claudin 18.2 protein expression has become increasingly clinically relevant nowadays since the impressive therapeutic benefits of the claudin 18.2 antibody zolbetuximab have been widely recognized. Systematic studies evaluating its expression, including in vulvar cancer, are needed to understand whether such treatment strategies may eventually benefit patients with vulvar neoplasia.
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Affiliation(s)
- Gilbert Georg Klamminger
- Department of General and Special Pathology, Saarland University (USAAR) and Saarland University Medical Center (UKS), Homburg, Germany
- Department of Obstetrics and Gynecology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Annick Bitterlich
- Department of General and Special Pathology, Saarland University (USAAR) and Saarland University Medical Center (UKS), Homburg, Germany
| | - Meletios P Nigdelis
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center (UKS), Homburg, Germany
| | - Martin Ertz
- Department of General and Special Pathology, Saarland University (USAAR) and Saarland University Medical Center (UKS), Homburg, Germany
| | - Kim Yoo-Jin
- Department of General and Special Pathology, Saarland University (USAAR) and Saarland University Medical Center (UKS), Homburg, Germany
- Department of Pathology, Institute for Pathology GbR Kaiserslautern, Kaiserslautern, Germany
| | - Annette Hasenburg
- Department of Obstetrics and Gynecology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Mathias Wagner
- Department of General and Special Pathology, Saarland University (USAAR) and Saarland University Medical Center (UKS), Homburg, Germany
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Bova V, Mannino D, Salako AE, Esposito E, Filippone A, Scuderi SA. Casein Kinase 2 Inhibitor, CX-4945, Induces Apoptosis and Restores Blood-Brain Barrier Homeostasis in In Vitro and In Vivo Models of Glioblastoma. Cancers (Basel) 2024; 16:3936. [PMID: 39682125 DOI: 10.3390/cancers16233936] [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: 09/19/2024] [Revised: 10/21/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
Background: In oncology, casein kinase 2 (CK2), a serine/threonine kinase, has a dual action, regulating cellular processes and acting as an oncogenic promoter. Methods: This study examined the effect of CX-4945, a selective CK2 inhibitor, in a human U-87 glioblastoma (GBM) cell line, treated with CX-4945 (5, 10, and 15 μM) for 24 h. Similarly, the hCMEC/D3 cell line was used to mimic the blood-brain barrier (BBB), examining the ability of CX-4945 to restore BBB homeostasis, after stimulation with lipopolysaccharide (LPS) and then treated with CX-4945 (5, 10, and 15 μM). Results: We reported that CX-4945 reduced the proliferative activity and modulated the main pathways involved in tumor progression including apoptosis. Furthermore, in confirmation of the in vitro study, performing a xenograft model, we demonstrated that CX-4945 exerted promising antiproliferative effects, also restoring the tight junctions' expression. Conclusions: These new insights into the molecular signaling of CK2 in GBM and BBB demonstrate that CX-4945 could be a promising approach for future GBM therapy, not only in the tumor microenvironment but also at the BBB level.
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Affiliation(s)
- Valentina Bova
- Department of Chemical, Biological, Pharmaceutical, Environmental Science, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy
| | - Deborah Mannino
- Department of Chemical, Biological, Pharmaceutical, Environmental Science, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy
| | - Ayomide E Salako
- Department of Chemical, Biological, Pharmaceutical, Environmental Science, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy
- Department of Statistics, Computer Science, Applications (DiSIA), University of Florence, 50121 Firenze, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical, Environmental Science, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy
| | - Alessia Filippone
- Department of Chemical, Biological, Pharmaceutical, Environmental Science, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy
| | - Sarah A Scuderi
- Department of Chemical, Biological, Pharmaceutical, Environmental Science, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy
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Xie Y, Shang S, Luan W, Ma J, Yang H, Qian Q, Wu Z, Li X. Apple Polyphenol Extracts Attenuated Depressive-Like Behaviors of High-Sucrose Diet Feeding Mice by Farnesoid X Receptor-Mediated Modulation of Bile Acid Circulation within the Liver-Gut-Brain Axis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:25118-25134. [PMID: 39475537 DOI: 10.1021/acs.jafc.4c07035] [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: 11/14/2024]
Abstract
Although the association between high-sugar diets and depression has been verified, few studies have explored the antidepressant mechanisms of apple polyphenol extracts (APE). Therefore, fifty-four C57BL/6 male mice aged 5 weeks were randomly assigned into five groups: the control group with the standard diet (CON), the constant high-sucrose diet group (HSD), the "2 + 5" alternate diet group (A-HSD), and the 500 mg/(kg·bw) APE treatment for the HSD group (APE) and the A-HSD group (A-APE), respectively. The data of hypothalamic-pituitary-adrenal (HPA) axis function and behavioral experiments confirmed the success in the establishment of depression-like mouse models in both HSD and A-HSD groups, which were significantly alleviated after APE treatment. Meanwhile, APE reduced serum levels of corticosterone and adrenocorticotrophic hormone, alleviated histopathological damage of the liver, colon, and brain, respectively, elevated the protein expressions of Occludin, ZO-1, and MUC-2, and decreased Firmicutes/Bacteroidota ratio and Dubosiella abundance with the increased microbiota of Tannerellaceae_unclassified, Muribaculum, and Lachnospiraceae_unclassified. Moreover, APE treatment reduced Farnesoid X receptor (FXR) protein levels along with the increased expressions of CYP7A1 and TGR5, lowered the contents of serum and fecal total bile acids, and modulated fecal BA compositions, particularly glycocholic acid (GCA) and isolithocholic acid (ILCA). Thus, both the constant and alternate high-sucrose diets successfully induced depression-like behaviors in mice, and APE might be a potential nutraceutical to attenuate high-sucrose diet-induced depression by regulating BAs circulation within the liver-gut-brain axis mediated by FXR.
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Affiliation(s)
- Yisha Xie
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
- Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang 318000, China
| | - Siyuan Shang
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Wenxue Luan
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Jieyu Ma
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Hao Yang
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Qingfan Qian
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Zhengli Wu
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Xinli Li
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
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7
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Zhou X, Liu Q, Li Z, Liu X, Zhao Q, Wang Y, Wu F, Zhao G, Sun R, Guo X. The activation of adenosine monophosphate-activated protein kinase inhibits the migration of tongue squamous cell carcinoma cells by targeting Claudin-1 via epithelial-mesenchymal transition. Animal Model Exp Med 2024; 7:606-616. [PMID: 39017036 PMCID: PMC11528389 DOI: 10.1002/ame2.12444] [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: 02/26/2024] [Revised: 05/15/2024] [Accepted: 05/26/2024] [Indexed: 07/18/2024] Open
Abstract
BACKGROUND The role of Claudin-1 in tongue squamous cell carcinoma (TSCC) metastasis needs further clarification, particularly its impact on cell migration. Herein, our study aims to investigate the role of Claudin-1 in TSCC cell migration and its underlying mechanisms. METHODS 36 TSCC tissue samples underwent immunohistochemical staining for Claudin-1. Western blotting and immunofluorescence analyses were conducted to evaluate Claudin-1 expression and distribution in TSCC cells. Claudin-1 knockdown cell lines were established using short hairpin RNA transfection. Migration effects were assessed through wound healing assays. Furthermore, the expression of EMT-associated molecules was measured via western blotting. RESULTS Claudin-1 expression decreased as TSCC malignancy increased. Adenosine monophosphate-activated protein kinase (AMPK) activation led to increased Claudin-1 expression and membrane translocation, inhibiting TSCC cell migration and epithelial-mesenchymal transition (EMT). Conversely, Claudin-1 knockdown reversed these inhibitory effects on migration and EMT caused by AMPK activation. CONCLUSIONS Our results indicated that AMPK activation suppresses TSCC cell migration by targeting Claudin-1 and EMT pathways.
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Affiliation(s)
- Xin‐Yue Zhou
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
- Hubei Shizhen LaboratoryWuhanHubeiChina
| | - Qiu‐Ming Liu
- Sino‐German Biomedical CenterHubei University of TechnologyWuhanChina
- Center of Applied BiotechnologyWuhan Institute of BioengineeringWuhanChina
| | - Zhuang Li
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Xia‐Yang Liu
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Qi‐Wei Zhao
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Yu Wang
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Feng‐Hua Wu
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
- Hubei Shizhen LaboratoryWuhanHubeiChina
| | - Gang Zhao
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Rui Sun
- Department of Stomatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuanChina
- Department of Oral and Maxillofacial SurgeryShanxi Provincial People's HospitalTaiyuanChina
| | - Xiao‐Hong Guo
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
- Hubei Shizhen LaboratoryWuhanHubeiChina
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Li Y, Mei M, Wang Q, Gen L, Hao K, Zhong R, Mo T, Jiang J, Zhu W. Structural characteristics and anti-photoaging effect of Pyracantha fortuneana fruit polysaccharides in vitro and in vivo. Int J Biol Macromol 2024; 278:134123. [PMID: 39053831 DOI: 10.1016/j.ijbiomac.2024.134123] [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: 01/04/2024] [Revised: 05/23/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024]
Abstract
Pyracantha fortuneana is a cultivated pant extensively cultivated worldwide for its ornamental value and ecological benefits. In this study, a polysaccharide with anti-photoaging activity was extracted and purified from P. fortuneana fruit (PPFP). The structural constitution of PPFP was elucidated by molecular weight determination, FT-IR, monosaccharide composition analysis, smith degradation, methylation, and NMR spectroscopy. The results revealed that PPFP is a macromolecular polysaccharide with a weight-average molecular weight of 70,895 Da. The PPFP is predominantly characterized by →3,6)-β-Galp-(1→, →5,3)-α-Araf-(1 → and →4,2)-α-Xylp-(1→, →4)-β-Galp-(1 → and →4)-β-GalpA-(1 → glycosidic linkages, with t-α-Araf-(1 → and t-α-Glcp-(1 → terminal units. The anti-photoaging activity and potential mechanism of action of PPFP was investigated in vitro and in vivo. Results showed that PPFP exerted anti-photoaging effect on UVB-damaged HaCaT cells by ameliorating cell apoptosis, regulating the mitochondrial membrane potential and oxidative stress level, alleviating the phosphorylation level of the proteins in MAPK pathways, and repairing the expression of tight junction proteins. Moreover, PPFP enhanced the lifespan and diminished the oxidative stress in UVB-injured Caenorhabditis elegans. Collectively, this study comprehensively elucidates the anti-photodamaging potential of P. fortuneana fruit polysaccharide and offers a novel plant-derived adjuvant therapy for the treating photodamage.
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Affiliation(s)
- Yimeng Li
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China; The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Synthetic Enzymes and Natural Products Center, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore
| | - Manxue Mei
- The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Qianhui Wang
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Longmei Gen
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Kexin Hao
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Ruifang Zhong
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Tongxin Mo
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jianguo Jiang
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China.
| | - Wei Zhu
- The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Shunde Hospital of Guangzhou University of Chinese Medicine, Guangzhou 528329, China.
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9
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Hao JL, Li XY, Liu YT, Lang JX, Liu DJ, Zhang CD. Antibody-drug conjugates in gastric cancer: from molecular landscape to clinical strategies. Gastric Cancer 2024; 27:887-906. [PMID: 38963593 DOI: 10.1007/s10120-024-01529-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
Antibody-drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics.
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Affiliation(s)
- Jia-Lin Hao
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Xin-Yun Li
- Clinical Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Yu-Tong Liu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110022, China
| | - Ji-Xuan Lang
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Di-Jie Liu
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Chun-Dong Zhang
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
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10
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Li D, Zhang Z, Zhang C, Guo Q, Chen C, Peng X. Unraveling the connection between Hashimoto's Thyroiditis and non-alcoholic fatty liver disease: exploring the role of CD4 +central memory T cells through integrated genetic approaches. Endocrine 2024; 85:751-765. [PMID: 38400881 DOI: 10.1007/s12020-024-03745-z] [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: 12/10/2023] [Accepted: 02/12/2024] [Indexed: 02/26/2024]
Abstract
PURPOSE Exploring the connection between Hashimoto's thyroiditis (HT) and non-alcoholic fatty liver disease (NAFLD) through integrated genetic approaches. METHODS We utilized integrated genetic approaches, such as single-cell RNA sequencing (scRNA-seq) data analysis, Mendelian Randomization (MR), colocalization analysis, cell communication, and metabolic analyses, to investigate potential correlations between HT and NAFLD. RESULTS Through the integrated analysis of scRNA-seq data from individuals with HT, NAFLD, and healthy controls, we observed an upregulation in the proportion of CD4+central memory (CD4+CM) T cells among T cells in both diseases. A total of 63 differentially expressed genes (DEGs) were identified in the CD4+CM cells after the differential analysis. By using MR, 8 DEGs (MAGI3, CSGALNACT1, CAMK4, GRIP1, TRAT1, IL7R, ERN1, and MB21D2) were identified to have a causal relationship with HT, and 4 DEGs (MAGI3, RCAN3, DOCK10, and SAMD12) had a causal relationship with NAFLD. MAGI3 was found to be causally linked to both HT and NAFLD. Therefore, MAGI3 was designated as the marker gene. Reverse MR and Steiger filtering showed no evidence of reverse causality. Colocalization analyses further indicated close links between MAGI3 and HT as well as NAFLD. Finally, based on the expression levels of MAGI3, we stratified CD4+CM cells into two subsets: MAGI3+CD4+CM cells and MAGI3-CD4+CM cells. Functional analyses revealed significant differences between the two subsets, potentially related to the progression of the two diseases. CONCLUSION This study delves into the potential connections between HT and NAFLD through integrated genetic methods. Our research reveals an elevated proportion of CD4+CM cells within T cells in both HT and NAFLD. Through MR and colocalization analysis, we identify specific genes causally linked to HT and NAFLD, such as MAGI3. Ultimately, based on MAGI3 expression levels, we categorize CD4+CM cells into MAGI3+CD4+CM cells and MAGI3-CD4+CM cells, uncovering significant differences between them through functional analyses.
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Affiliation(s)
- Dairui Li
- Department of Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Zeji Zhang
- Department of Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Cheng Zhang
- Department of Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qiannan Guo
- Department of Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Chen Chen
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Xinzhi Peng
- Department of Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
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11
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Benyamini P. Phylogenetic Tracing of Evolutionarily Conserved Zonula Occludens Toxin Reveals a "High Value" Vaccine Candidate Specific for Treating Multi-Strain Pseudomonas aeruginosa Infections. Toxins (Basel) 2024; 16:271. [PMID: 38922165 PMCID: PMC11209546 DOI: 10.3390/toxins16060271] [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: 05/03/2024] [Revised: 06/09/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
Extensively drug-resistant Pseudomonas aeruginosa infections are emerging as a significant threat associated with adverse patient outcomes. Due to this organism's inherent properties of developing antibiotic resistance, we sought to investigate alternative strategies such as identifying "high value" antigens for immunotherapy-based purposes. Through extensive database mining, we discovered that numerous Gram-negative bacterial (GNB) genomes, many of which are known multidrug-resistant (MDR) pathogens, including P. aeruginosa, horizontally acquired the evolutionarily conserved gene encoding Zonula occludens toxin (Zot) with a substantial degree of homology. The toxin's genomic footprint among so many different GNB stresses its evolutionary importance. By employing in silico techniques such as proteomic-based phylogenetic tracing, in conjunction with comparative structural modeling, we discovered a highly conserved intermembrane associated stretch of 70 amino acids shared among all the GNB strains analyzed. The characterization of our newly identified antigen reveals it to be a "high value" vaccine candidate specific for P. aeruginosa. This newly identified antigen harbors multiple non-overlapping B- and T-cell epitopes exhibiting very high binding affinities and can adopt identical tertiary structures among the least genetically homologous P. aeruginosa strains. Taken together, using proteomic-driven reverse vaccinology techniques, we identified multiple "high value" vaccine candidates capable of eliciting a polarized immune response against all the P. aeruginosa genetic variants tested.
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Affiliation(s)
- Payam Benyamini
- Department of Health Sciences at Extension, University of California Los Angeles, 1145 Gayley Ave., Los Angeles, CA 90024, USA
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12
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Szabó A, De Vlieghere E, Costa PF, Geurs I, Dewettinck K, Maes L, Laukens D, Van Vlierberghe S. Effect of Porosity on the Colonization of Digital Light-Processed 3D Hydrogel Constructs toward the Development of a Functional Intestinal Model. Biomacromolecules 2024; 25:2863-2874. [PMID: 38564884 DOI: 10.1021/acs.biomac.4c00019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
With the rapid increase of the number of patients with gastrointestinal diseases in modern society, the need for the development of physiologically relevant in vitro intestinal models is key to improve the understanding of intestinal dysfunctions. This involves the development of a scaffold material exhibiting physiological stiffness and anatomical mimicry of the intestinal architecture. The current work focuses on evaluating the scaffold micromorphology of gelatin-methacryloyl-aminoethyl-methacrylate-based nonporous and porous intestinal 3D, intestine-like constructs, fabricated via digital light processing, on the cellular response. To this end, Caco-2 intestinal cells were utilized in combination with the constructs. Both porous and nonporous constructs promoted cell growth and differentiation toward enterocyte-like cells (VIL1, ALPI, SI, and OCLD expression showed via qPCR, ZO-1 via immunostaining). The porous constructs outperformed the nonporous ones regarding cell seeding efficiency and growth rate, confirmed by MTS assay, live/dead staining, and TEER measurements, due to the presence of surface roughness.
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Affiliation(s)
- Anna Szabó
- Polymer Chemistry and Biomaterials Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Ghent 9000, Belgium
| | - Elly De Vlieghere
- Polymer Chemistry and Biomaterials Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Ghent 9000, Belgium
| | | | - Indi Geurs
- Department of Food Technology, Safety and Health, Food Structure & Function Research Group, Ghent University, Gent 9000, Belgium
| | - Koen Dewettinck
- Department of Food Technology, Safety and Health, Food Structure & Function Research Group, Ghent University, Gent 9000, Belgium
| | - Laure Maes
- IBD Research Unit, Ghent Gut Inflammation Group (GGIG), Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium
| | - Debby Laukens
- IBD Research Unit, Ghent Gut Inflammation Group (GGIG), Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium
| | - Sandra Van Vlierberghe
- Polymer Chemistry and Biomaterials Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Ghent 9000, Belgium
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Ongun M, Lokras AG, Baghel S, Shi Z, Schmidt ST, Franzyk H, Rades T, Sebastiani F, Thakur A, Foged C. Lipid nanoparticles for local delivery of mRNA to the respiratory tract: Effect of PEG-lipid content and administration route. Eur J Pharm Biopharm 2024; 198:114266. [PMID: 38499255 DOI: 10.1016/j.ejpb.2024.114266] [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: 12/18/2023] [Revised: 03/11/2024] [Accepted: 03/13/2024] [Indexed: 03/20/2024]
Abstract
Design of inhalable mRNA therapeutics is promising because local administration in the respiratory tract is minimally invasive and induces a local response. However, several challenges related to administration via inhalation and respiratory tract barriers have so far prevented the progress of inhaled mRNA therapeutics. Here, we investigated factors of importance for lipid nanoparticle (LNP)-mediated delivery of mRNA to the respiratory tract. We hypothesized that: (i) the PEG-lipid content is important for providing colloidal stability during aerosolization and for mucosal delivery, (ii) the PEG-lipid contentinfluences the expression of mRNA-encoded protein in the lungs, and (iii) the route of administration (nasal versus pulmonary) affects mRNA delivery in the lungs. In this study, we aimed to optimize the PEG-lipid content for mucosal delivery and to investigatethe effect of administration route on the kinetics of protein expression. Our results show that increasing the PEG-lipid content improves the colloidal stability during the aerosolization process, but has a negative impact on the transfection efficiencyin vitro. The kinetics of protein expressionin vivois dependent on the route of administration, and we found that pulmonaryadministration of mRNA-LNPs to mice results inmore durable protein expression than nasaladministration. These results demonstrate that the design of the delivery system and the route of administration are importantfor achieving high mRNA transfection efficiency in the respiratory tract.
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Affiliation(s)
- Melike Ongun
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Abhijeet Girish Lokras
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Saahil Baghel
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Zhenning Shi
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Signe Tandrup Schmidt
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark
| | - Henrik Franzyk
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen Ø, Denmark
| | - Thomas Rades
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Federica Sebastiani
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark; Division of Physical Chemistry, Department of Chemistry, Lund University, 22100 Lund, Sweden
| | - Aneesh Thakur
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Camilla Foged
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
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Wang J, Li TL, Chang PF, Gao YQ, Fan JS, Zhang CH, Zhu HY. Clinical effects and mechanisms of a Chinese patent medicine, Tongxinluo capsule, as an adjuvant treatment in coronary heart disease. Heliyon 2024; 10:e27460. [PMID: 38533036 PMCID: PMC10963209 DOI: 10.1016/j.heliyon.2024.e27460] [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: 09/10/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/28/2024] Open
Abstract
Coronary heart disease (CHD) is the leading cause of death globally, posing a serious threat to human health. However, the current treatment approaches available for CHD fall short of the ideal results. Tongxinluo (TXL) is a traditional Chinese medicine (TCM) that has been employed in the clinical treatment of cardiovascular and cerebrovascular diseases (such as angina pectoris, stroke, etc.) in China for many years and holds great potential as a prospective treatment. TXL either as a standalone treatment or in combination with interventions recommended in CHD guidelines has been shown to be effective and well tolerated in clinical trials for CHD. Drawing on the evidence from clinical trials and experimental studies, this review will focus on the cardiovascular protective properties and related mechanisms of TXL. By searching 8 Chinese and English databases, more than 4000 articles were retrieved. These articles were categorized, then read, and finally written into this review. In this review, the pharmacological properties of TXL include regulation of blood lipids, improvement of endothelial function, anti-inflammatory, antioxidant, inhibition of apoptosis and regulation of autophagy, anti-fibrosis, promotion of angiogenesis, and modulation of exosome communication. The information provided in this review will help the reader to comprehend better the insights that TCM has developed over time in practice and provide new perspectives for the treatment of CHD.
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Affiliation(s)
- Jing Wang
- Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, 100700, China
| | - Tian Li Li
- China-Japan Friendship Hospital, Beijing, 100029, China
| | - Pei Fen Chang
- Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, 100700, China
| | - Yu Qian Gao
- Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, 100700, China
| | - Jia Sai Fan
- Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, 100700, China
| | - Chen Hao Zhang
- China Academy of Chinese Medicine Science Affiliated Wangjing Hospital, Beijing, 100102, China
| | - Hai Yan Zhu
- Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, 100700, China
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Nagaoka Y, Oshiro K, Yoshino Y, Matsunaga T, Endo S, Ikari A. Activation of the TGF-β1/EMT signaling pathway by claudin-1 overexpression reduces doxorubicin sensitivity in small cell lung cancer SBC-3 cells. Arch Biochem Biophys 2024; 751:109824. [PMID: 37984759 DOI: 10.1016/j.abb.2023.109824] [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: 09/23/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 11/22/2023]
Abstract
Small-cell lung cancer (SCLC), which accounts for about 15 % of all lung cancers, progresses more rapidly than other histologic types and is rarely detected at an operable early stage. Therefore, chemotherapy, radiation therapy, or their combination are the primary treatments for this type of lung cancer. However, the tendency to acquire resistance to anticancer drugs is a severe problem. Recently, we found that an intercellular adhesion molecule, claudin (CLDN) 1, known to be involved in the migration and invasion of lung cancer cells, is involved in the acquisition of anticancer drug resistance. In the present study, we investigated the effect of CLDN1 on the anticancer-drug sensitivity of SCLC SBC-3 cells. Since epithelial-mesenchymal transition (EMT), which is involved in cancer cell migration and invasion, is well known for its involvement in anticancer-drug sensitivity via inhibition of apoptosis, we also examined EMT involvement in decreased anticancer-drug sensitivity by CLDN1. Sensitivity to doxorubicin (DOX) in SBC-3 cells was significantly decreased by CLDN1 overexpression. CLDN1 overexpression resulted in increased TGF-β1 levels, enhanced EMT induction, and increased migratory potency of SBC-3 cells. The decreased sensitivity of SBC-3 cells to anticancer drugs upon TGF-β1 treatment suggested that activation of the TGF-β1/EMT signaling pathway by CLDN1 causes the decreased sensitivity to anticancer drugs and increased migratory potency. Furthermore, treatments with antiallergic agents tranilast and zoledronic acid, known EMT inhibitors, significantly mitigated the decreased sensitivity of CLDN1-overexpressing SBC-3 cells to DOX. These results suggest that EMT inhibitors might effectively overcome reduced sensitivity to anticancer drugs in CLDN1-overexpressing SCLC cells.
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Affiliation(s)
- Yuri Nagaoka
- Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Kotone Oshiro
- Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Yuta Yoshino
- Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Toshiyuki Matsunaga
- Laboratory of Bioinformatics, Gifu Pharmaceutical University, Gifu 502-8585, Japan
| | - Satoshi Endo
- Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan; Center for One Medicine Innovative Translational Research (COMIT), Gifu Pharmaceutical University, Gifu 501-1196, Japan.
| | - Akira Ikari
- Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
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16
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Gartling G, Nakamura R, Sayce L, Kimball EE, Wilson A, Schneeberger S, Zimmerman Z, Garabedian MJ, Branski RC, Rousseau B. Acute Effects of Systemic Glucocorticoids on the Vocal Folds in a Pre-Clinical Model. Ann Otol Rhinol Laryngol 2024; 133:87-96. [PMID: 37497827 PMCID: PMC10818023 DOI: 10.1177/00034894231188571] [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: 07/28/2023]
Abstract
OBJECTIVES/HYPOTHESIS Systemic glucocorticoids (GC)s are employed to treat various voice disorders. However, GCs have varying pharmacodynamic properties with adverse effects ranging from changes in epithelial integrity, skeletal muscle catabolism, and altered body weight. We sought to characterize the acute temporal effects of systemic dexamethasone and methylprednisolone on vocal fold (VF) epithelial glucocorticoid receptor (GR) nuclear translocation, epithelial tight junction (ZO-1) expression, thyroarytenoid (TA) muscle fiber morphology, and body weight using an established pre-clinical model. We hypothesized dexamethasone and methylprednisolone will elicit changes in VF epithelial GR nuclear translocation, epithelial ZO-1 expression, TA muscle morphology, and body weight compared to placebo-treated controls. METHODS Forty-five New Zealand white rabbits received intramuscular injections of methylprednisolone (4.5 mg; n = 15), dexamethasone (450 µg; n = 15), or volume matched saline (n = 15) into the iliocostalis/longissimus muscle for 6 consecutive days. Vocal folds from 5 rabbits from each treatment group were harvested at 1-, 3-, or 7 days following the final injection and subjected to immunohistochemistry for ZO-1 and GR as well as TA muscle fiber cross-sectional area (CSA) measures. RESULTS Dexamethasone increased epithelial GR nuclear translocation and ZO-1 expression 1-day following injections compared to methylprednisolone (P = .024; P = .012). Dexamethasone and methylprednisolone increased TA CSA 1-day following injections (P = .011). Methylprednisolone decreased body weight 7 days following injections compared to controls (P = .004). CONCLUSIONS Systemic dexamethasone may more efficiently activate GR in the VF epithelium with a lower risk of body weight loss, suggesting a role for more refined approaches to GC selection for laryngeal pathology.
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Affiliation(s)
- Gary Gartling
- Communication Science and Disorders, University of Pittsburgh, Pittsburgh, PA, USA
- Rehabilitation Medicine, NYU Grossman School of Medicine, New York, NY, USA
| | - Ryosuke Nakamura
- Rehabilitation Medicine, NYU Grossman School of Medicine, New York, NY, USA
| | - Lea Sayce
- Communication Science and Disorders, University of Pittsburgh, Pittsburgh, PA, USA
| | - Emily E. Kimball
- Hearing and Speech Sciences, Vanderbilt University, Nashville, TN, USA
- Otolaryngology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Azure Wilson
- Communication Science and Disorders, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven Schneeberger
- Plastic and Reconstructive Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Zachary Zimmerman
- Communication Science and Disorders, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael J. Garabedian
- Microbiology, NYU Grossman School of Medicine, New York, NY, USA
- Department of Urology, NYU Grossman School of Medicine, New York, NY, USA
| | - Ryan C. Branski
- Rehabilitation Medicine, NYU Grossman School of Medicine, New York, NY, USA
- Otolaryngology-Head and Neck Surgery, NYU Grossman School of Medicine, New York, NY, USA
| | - Bernard Rousseau
- Doisy College of Health Sciences, Saint Louis University, St. Louis, MO, USA
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17
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Corley C, McElroy T, Sridharan B, Trujillo M, Simmons P, Kandel S, Sykes DJ, Robeson MS, Allen AR. Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior. Front Neurosci 2023; 17:1212791. [PMID: 37869506 PMCID: PMC10587567 DOI: 10.3389/fnins.2023.1212791] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 09/08/2023] [Indexed: 10/24/2023] Open
Abstract
Introduction Chemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses. Methods Forced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers. Results and discussion We observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut.
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Affiliation(s)
- Christa Corley
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Taylor McElroy
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Bhavana Sridharan
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Madison Trujillo
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Pilar Simmons
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Sangam Kandel
- Department of Bioinformatics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | | | - Michael S. Robeson
- Department of Bioinformatics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Antiño R. Allen
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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Voigt AL, de Lima e Martins Lara N, Dobrinski I. Comparing the adult and pre-pubertal testis: Metabolic transitions and the change in the spermatogonial stem cell metabolic microenvironment. Andrology 2023; 11:1132-1146. [PMID: 36690000 PMCID: PMC10363251 DOI: 10.1111/andr.13397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/13/2023] [Accepted: 01/19/2023] [Indexed: 01/25/2023]
Abstract
BACKGROUND Survivors of childhood cancer often suffer from infertility. While sperm cryopreservation is not feasible before puberty, the patient's own spermatogonial stem cells could serve as a germ cell reservoir, enabling these patients to father their own children in adulthood through the isolation, in vitro expansion, and subsequent transplantation of spermatogonial stem cells. However, this approach requires large numbers of stem cells, and methods for successfully propagating spermatogonial stem cells in the laboratory are yet to be established for higher mammals and humans. The improvement of spermatogonial stem cell culture requires deeper understanding of their metabolic requirements and the mechanisms that regulate metabolic homeostasis. AIM This review gives a summary on our knowledge of spermatogonial stem cell metabolism during maintenance and differentiation and highlights the potential influence of Sertoli cell and stem cell niche maturation on spermatogonial stem cell metabolic requirements during development. RESULTS AND CONCLUSIONS Fetal human spermatogonial stem cell precursors, or gonocytes, migrate into the seminiferous cords and supposedly mature to adult stem cells within the first year of human development. However, the spermatogonial stem cell niche does not fully differentiate until puberty, when Sertoli cells dramatically rearrange the architecture and microenvironment within the seminiferous epithelium. Consequently, pre-pubertal and adult spermatogonial stem cells experience two distinct niche environments potentially affecting spermatogonial stem cell metabolism and maturation. Indeed, the metabolic requirements of mouse primordial germ cells and pig gonocytes are distinct from their adult counterparts, and novel single-cell RNA sequencing analysis of human and porcine spermatogonial stem cells during development confirms this metabolic transition. Knowledge of the metabolic requirements and their changes and regulation during spermatogonial stem cell maturation is necessary to implement laboratory-based techniques and enable clinical use of spermatogonial stem cells. Based on the advancement in our understanding of germline metabolism circuits and maturation events of niche cells within the testis, we propose a new definition of spermatogonial stem cell maturation and its amendment in the light of metabolic change.
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Affiliation(s)
- Anna Laura Voigt
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; and Faculty of Veterinary Medicine, University of Calgary, AB, Canada
| | - Nathalia de Lima e Martins Lara
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; and Faculty of Veterinary Medicine, University of Calgary, AB, Canada
| | - Ina Dobrinski
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine; and Faculty of Veterinary Medicine, University of Calgary, AB, Canada
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Takasawa A, Takasawa K, Murata M, Osanai M, Sawada N. Emerging roles of transmembrane-type tight junction proteins in cancers. Pathol Int 2023; 73:331-340. [PMID: 37449777 DOI: 10.1111/pin.13349] [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: 04/19/2023] [Accepted: 06/06/2023] [Indexed: 07/18/2023]
Abstract
Tight junctions (TJs) are the most apical components of the cell-cell adhesion machinery in epithelial and endothelial cells and they play essential roles in homeostasis. Recent studies have revealed that aberrant expression of tight junction proteins (TJPs) is frequently observed in various type of cancers. Here we review cancer-associated aberrant expression of TJPs with focus on transmembrane-type TJPs including claudins, junctional adhesion molecule-A (JAM-A), and occludin. Some transmembrane-type TJPs are upregulated at the early neoplastic stage and their expression persists during dedifferentiation. Aberrant expression of TJPs contributes to proliferation, invasion, and dysregulated signaling of cancer cells. In addition to an increase in their expression level, their localization is altered from a TJ-restricted pattern to distribution throughout the whole cell membrane, making them suitable as therapeutic targets. Extracellular domains of transmembrane-type TJPs can be approached by target drugs not only from the lumen side (apical side) but also from the extracellular matrix side (basal side), including blood vessels. Aberrantly expressed TJPs are potential useful diagnostic markers as well as therapeutic targets for cancers.
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Affiliation(s)
- Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Diagnostic Pathology, Tokeidai Memorial Hospital, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Norimasa Sawada
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Zhang D, Zhang J, Zhang J, Ji X, Qi Q, Xu J, Pan Y, Liu X, Sun F, Zeng R, Dong L. Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption. Respir Res 2023; 24:182. [PMID: 37434162 DOI: 10.1186/s12931-023-02488-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 07/01/2023] [Indexed: 07/13/2023] Open
Abstract
Alveolar epithelial barrier is a potential therapeutic target for acute respiratory distress syndrome (ARDS). However, an effective intervention against alveolar epithelial barrier has not been developed. Here, based on single-cell RNA and mRNA sequencing results, death receptor 3 (DR3) and its only known ligand tumor necrosis factor ligand-associated molecule 1A (TL1A) were significantly reduced in epithelium from an ARDS mice and cell models. The apparent reduction in the TL1A/DR3 axis in lungs from septic-ARDS patients was correlated with the severity of the disease. The examination of knockout (KO) and alveolar epithelium conditional KO (CKO) mice showed that TL1A deficiency exacerbated alveolar inflammation and permeability in lipopolysaccharide (LPS)-induced ARDS. Mechanistically, TL1A deficiency decreased glycocalyx syndecan-1 and tight junction-associated zonula occludens 3 by increasing cathepsin E level for strengthening cell-to-cell permeability. Additionally, DR3 deletion aggravated barrier dysfunction and pulmonary edema in LPS-induced ARDS through the above mechanisms based on the analyses of DR3 CKO mice and DR3 overexpression cells. Therefore, the TL1A/DR3 axis has a potential value as a key therapeutic signaling for the protection of alveolar epithelial barrier.
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Affiliation(s)
- Dong Zhang
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Jianning Zhang
- Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Jintao Zhang
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Xiang Ji
- Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Qian Qi
- Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Jiawei Xu
- Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Yun Pan
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Xiaofei Liu
- Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Fang Sun
- Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Rong Zeng
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Liang Dong
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China.
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21
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Li J, Lan Z, Liao W, Horner JW, Xu X, Liu J, Yoshihama Y, Jiang S, Shim HS, Slotnik M, LaBella KA, Wu CJ, Dunner K, Hsu WH, Lee R, Khanduri I, Terranova C, Akdemir K, Chakravarti D, Shang X, Spring DJ, Wang YA, DePinho RA. Histone demethylase KDM5D upregulation drives sex differences in colon cancer. Nature 2023; 619:632-639. [PMID: 37344599 PMCID: PMC10529424 DOI: 10.1038/s41586-023-06254-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 05/24/2023] [Indexed: 06/23/2023]
Abstract
Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP)2, revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
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Affiliation(s)
- Jiexi Li
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhengdao Lan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wenting Liao
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - James W Horner
- TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xueping Xu
- TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jielin Liu
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yohei Yoshihama
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shan Jiang
- TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hong Seok Shim
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Max Slotnik
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kyle A LaBella
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chang-Jiun Wu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kenneth Dunner
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wen-Hao Hsu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rumi Lee
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Isha Khanduri
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher Terranova
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kadir Akdemir
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Deepavali Chakravarti
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaoying Shang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Denise J Spring
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Y Alan Wang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Indiana University, Indianapolis, IN, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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22
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Dong ZX, Chan SH, Chen SN, Li M, Zhang XD, Liu XQ. TJP1 promotes vascular mimicry in bladder cancer by facilitating VEGFA expression and transcriptional activity through TWIST1. Transl Oncol 2023; 32:101666. [PMID: 37031603 PMCID: PMC10119961 DOI: 10.1016/j.tranon.2023.101666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 03/11/2023] [Accepted: 03/27/2023] [Indexed: 04/11/2023] Open
Abstract
Tight junction protein 1 (TJP1) is a recently identified prominent regulator of bladder cancer (BLCA) angiogenesis and tumorigenesis. Vascular mimicry (VM) is a newly described tumor feature and is correlated with an increased risk of tumor metastasis. However, the relationship between TJP1 expression and VM in bladder cancer remains elusive. In the present study, we report a novel function for TJP1 in accommodating VM to promote tumor progression. We found that the elevated TJP1 expression was positively related to VM in patients and xenograft tumor models in bladder cancer. Enforced expression of TJP1 increased VM of BLCA cells in vitro and in vivo by elevating Vascular endothelial growth factor A (VEGFA) levels. Furthermore, VM induced by TJP1 overexpression was significantly blocked by the VEGFA and VEGFR inhibitors (Bevacizumab and Sunitinib). Mechanistically, TJP1 promoted VEGFA transcriptional and protein level in a TWIST1-dependent manner. Taken together, our study reveals that TJP1-regulated VEGFA overexpression may indicate a potential therapeutic target for clinical intervention in the early tumor neovascularization of bladder cancer.
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Affiliation(s)
- Zhao-Xia Dong
- Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Sze-Hoi Chan
- Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Shu-Na Chen
- Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Miao Li
- Department of Hematology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
| | - Xing-Ding Zhang
- Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China.
| | - Xue-Qi Liu
- Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China.
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Arai W, Konno T, Kohno T, Kodera Y, Tsujiwaki M, Shindo Y, Chiba H, Miyajima M, Sakuma Y, Watanabe A, Kojima T. Downregulation of angulin-1/LSR induces malignancy via upregulation of EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma A549 cells. Oncotarget 2023; 14:261-275. [PMID: 36961882 PMCID: PMC10038356 DOI: 10.18632/oncotarget.27728] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2023] Open
Abstract
Abnormal expression of bicellular tight junction claudins, including claudin-2 are observed during carcinogenesis in human lung adenocarcinoma. However, little is known about the role of tricellular tight junction molecule angulin-1/lipolysis-stimulated lipoprotein receptor (LSR). In the lung adenocarcinoma tissues examined in the present study, expression of claudin-2 was higher than in normal lung tissues, while angulin-1/LSR was poorly or faintly expressed. We investigated how loss of angulin-1/LSR affects the malignancy of lung adenocarcinoma cell line A549 and normal human lung epithelial (HLE) cells. The EGF receptor tyrosine kinase inhibitor AG1478 prevented the increase of claudin-2 expression induced by EGF in A549 cells. Knockdown of LSR induced expression of claudin-2 at the protein and mRNA levels and AG1478 prevented the upregulation of claudin-2 in A549 cells. Knockdown of LSR induced cell proliferation, cell migration and cell metabolism in A549 cells. Knockdown of claudin-2 inhibited the cell proliferation but did not affect the cell migration or cell metabolism of A549 cells. The TGF-β type I receptor inhibitor EW-7197 prevented the decrease of LSR and claudin-2 induced by TGF-β1 in A549 cells and 2D culture of normal HLE cells. EW-7197 prevented the increase of cell migration and cell metabolism induced by TGF-β1 in A549 cells. EW-7197 prevented the increase of epithelial permeability of FITC-4kD dextran induced by TGF-β1 in 2.5D culture of normal HLE cells. In conclusion, downregulation of angulin-1/LSR induces malignancy via EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma.
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Affiliation(s)
- Wataru Arai
- Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takumi Konno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Kohno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuki Kodera
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Mitsuhiro Tsujiwaki
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuma Shindo
- Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Miyajima
- Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuji Sakuma
- Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Atsushi Watanabe
- Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takashi Kojima
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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24
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Liu Y, Li P, Jiang T, Li Y, Wang Y, Cheng Z. Epidermal growth factor receptor in asthma: A promising therapeutic target? Respir Med 2023; 207:107117. [PMID: 36626942 DOI: 10.1016/j.rmed.2023.107117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 01/09/2023]
Abstract
Activation of the epidermal growth factor receptor (EGFR) pathway is involved in the pathogenesis of asthma. Although decades of intensive research have focused on the role of EGFR in asthma, the specific mechanisms and pathways of EGFR signaling remain unclear. Various reports have indicated that inhibition of EGFR improves the pathological features in asthma models. However, extending these experimental findings to clinical applications is difficult. Several measures can be adopted to promote clinical application of EGFR inhibitors. This review focuses on the role of EGFR in the pathogenesis of asthma and the development of a potentially novel therapeutic target for asthma.
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Affiliation(s)
- Ye Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pengfei Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Tianci Jiang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yue Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yu Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Zhe Cheng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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25
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Fan Y, Ju T, Bhardwaj T, Korver DR, Willing BP. Week-Old Chicks with High Bacteroides Abundance Have Increased Short-Chain Fatty Acids and Reduced Markers of Gut Inflammation. Microbiol Spectr 2023; 11:e0361622. [PMID: 36719194 PMCID: PMC10100795 DOI: 10.1128/spectrum.03616-22] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 01/08/2023] [Indexed: 02/01/2023] Open
Abstract
As important commensals in the chicken intestine, Bacteroides are essential complex carbohydrate degraders, and short-chain fatty acid (SCFA) producers that are highly adapted to the distal gut. Previous studies have shown large variation in Bacteroides abundance in young chickens. However, limited information is available regarding how this variation affects the gut microbiome and host immunity. To investigate how elevated or depleted Bacteroides levels affect gut microbial functional capacity and impact host response, we sampled 7-day-old broiler chickens from 14 commercial production flocks. Week-old broiler chickens were screened and birds with low Bacteroides (LB) and high Bacteroides (HB) abundance were identified via 16S rRNA gene amplicon sequencing and quantitative PCR (qPCR) assays. Cecal microbial functionality and SCFA concentration of chickens with distinct cecal Bacteroides abundance were profiled by shotgun metagenomic sequencing and gas chromatography, respectively. The intestinal immune responses of LB and HB chickens were assessed via reverse transcription qPCR. Results showed that the gut microbiota of the LB group had increased abundance of lactic acid bacteria pyruvate fermentation pathway, whereas complex polysaccharide degradation and SCFA production pathways were enriched in the HB group (P < 0.05), which was supported by increased SCFA concentrations in the ceca of HB chickens (P < 0.05). HB chickens also showed decreased expression of interleukin-1β and increased expression of interleukin-10 and tight-junction protein claudin-1 (P < 0.05). Overall, the results indicated that elevated Bacteroides may benefit the 7-day broiler gut and that further work should be done to confirm the causal role of Bacteroides in the observed positive outcomes. IMPORTANCE To date, limited information is available comparing distinct Bacteroides compositions in the chicken gut microbial communities, particularly in the context of microbial functional capacities and host responses. This study showed that possessing a microbiome with elevated Bacteroides in early life may confer beneficial effects to the chicken host, particularly in improving SCFA production and gut health. This study is among the first metagenomic studies focusing on the early life chicken gut microbiota structure, microbial functionality, and host immune responses. We believe that it will offer insights to future studies on broiler gut microbial population and their effects on host health.
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Affiliation(s)
- Yi Fan
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Tingting Ju
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Tulika Bhardwaj
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Douglas R. Korver
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Benjamin P. Willing
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
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26
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Subacute Ruminal Acidosis as a Potential Factor that Induces Endometrium Injury in Sheep. Int J Mol Sci 2023; 24:ijms24021192. [PMID: 36674716 PMCID: PMC9861559 DOI: 10.3390/ijms24021192] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
The demand for economic benefits has led to an increase in the proportion of high-concentrate (HC) feed in the ruminant diet, resulting in an increased incidence of subacute ruminal acidosis (SARA). During SARA, a high concentration of lipopolysaccharide (LPS) translocated in the rumen induces a systemic inflammatory response. Inflammatory diseases, such as endometritis and mastitis, are often associated with SARA; however, in sheep, the mechanism of the effect of SARA on the endometrium has rarely been reported. Therefore, the aim of this study was to investigate, for the first time, the influence of LPS translocation on endometrial tight junctions (TJs) during SARA in sheep. The results showed that LPS and TNFα levels in the ruminal fluid, serum, and endometrial tissue supernatant during SARA increased, transcription levels of TLR4, NFκB, and TNFα in the endometrium increased, the protein expression level of claudin-1 in the endometrium increased, and the protein expression level of occludin decreased. 17β-estradiol (E2) inhibits claudin-1 protein expression and promotes occludin expression, and progesterone (P4) promotes claudin-1 protein expression and inhibits occludin protein expression. E2 and P4 regulate claudin-1 and occludin protein expression through their receptor pathways. Here, we found that LPS hindered the regulatory effect of E2 and P4 on endometrial TJs by inhibiting their receptor expression. The results of this study indicate that HC feeding can cause SARA-induced LPS translocation in sheep, increase susceptibility to systemic inflammation, induce the endometrial inflammatory response, and cause endometrial epithelial TJ damage directly and/or by obstructing E2 and P4 function. LPS translocation caused by SARA has also been suggested to induce an endometrial inflammatory response, resulting in endometrial epithelial barrier damage and physiological dysfunction, which seriously affects ruminant production. Therefore, this study provides new evidence that SARA is a potential factor that induces systemic inflammation in ruminants. It provides theoretical support for research on the prevention of endometritis in ruminants.
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27
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Fu R, Jiang X, Li G, Zhu Y, Zhang H. Junctional complexes in epithelial cells: sentinels for extracellular insults and intracellular homeostasis. FEBS J 2022; 289:7314-7333. [PMID: 34453866 DOI: 10.1111/febs.16174] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/13/2021] [Accepted: 08/27/2021] [Indexed: 01/13/2023]
Abstract
The cell-cell and cell-ECM junctions within the epithelial tissues are crucial anchoring structures that provide architectural stability, mechanical resistance, and permeability control. Their indispensable role as signaling hubs orchestrating cell shape-related changes such as proliferation, differentiation, migration, and apoptosis has also been well recognized. However, growing amount of evidence now suggests that the multitasking nature of epithelial junctions extends well beyond anchorage-dependent or cell shape change-related biological processes. In this review, we discuss the emerging roles of junctional complexes in regulating innate immune defense, stress resistance, and intracellular proteostasis of the epithelial cells, with emphasis on the upstream regulation of epithelial junctions on various aspects of the epithelial barrier.
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Affiliation(s)
- Rong Fu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, China
| | - Xiaowan Jiang
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, China
| | - Gang Li
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, China
| | - Yi Zhu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, China
| | - Huimin Zhang
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, China
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28
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Visualization of a novel human monoclonal antibody against Claudin-3 for targeting ovarian cancer. Nucl Med Biol 2022; 114-115:135-142. [PMID: 35501237 DOI: 10.1016/j.nucmedbio.2022.04.003] [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: 12/18/2021] [Revised: 03/23/2022] [Accepted: 04/04/2022] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Claudin-3 (CLDN3), a tight junction protein, regulates cell-to-cell interactions in epithelial or endothelial cell sheets. During tumorigenesis, epithelial cells are transformed, and tumor cells proliferate through out-of-plane division, resulting in external exposure of CLDN3. Since alterations of CLDN3 expression are associated with cancer progression and higher CLDN3 expression is observed in most ovarian cancers, we tested the feasibility of using a CLDN3-specific antibody as a novel imaging tracer. MATERIALS AND METHODS After reducing the CLDN3-specific antibodies to expose the -SH groups, click chemistry was used to conjugate the radioactive isotope 111In or the fluorescent protein FNR648. Human ovarian cancer OVCAR-3 and glioblastoma U87MG cells were used as CLDN3-positive and -negative cells. Flow cytometry was used to determine the CLDN3 IgG1 monoclonal antibody binding to both cell lines. OVCAR-3 cells were injected subcutaneously into mice to establish a xenograft model. 111In-labeled CLDN3 antibodies (370 kBq/50 μL) were administered intravenously into mice. After 24 h, organs, including tumors, were excised and measured with a γ-counter. Images were acquired with the IVIS optical imaging system and SPECT/CT. RESULTS The labeling efficiency of NOTA-111In and antibody-NOTA-111In was 98.52% and 100%, respectively. FNR648-labeled CLDN3 antibody bound to the cell surface of OVCAR-3 and U87MG with 83.4% and 5.7% specificity, respectively. In OVCAR-3 tumor xenografted mice, CLDN3 IgG1 antibody showed a 2.5-fold higher tumor uptake (20.4 ± 7.4% ID/g) than human IgG1 (8.8 ± 2.6% ID/g) at 24 h post injection. The CLDN3 antibody fluorescence signal in the tumor peaked at 24 h post injection. CONCLUSION We have successfully conjugated a radioisotope and a fluorescent protein with CLDN3-specific antibodies and verified the specific binding of labeled antibodies to OVCAR-3 tumors in a mouse model. Our data suggested that CLDN3-specific human monoclonal antibodies could be used as a useful theranostic tracer.
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29
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Faiad W, Soukkarieh C, Murphy DJ, Hanano A. Effects of dioxins on animal spermatogenesis: A state-of-the-art review. FRONTIERS IN REPRODUCTIVE HEALTH 2022; 4:1009090. [PMID: 36339774 PMCID: PMC9634422 DOI: 10.3389/frph.2022.1009090] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/28/2022] [Indexed: 11/23/2022] Open
Abstract
The male reproductive system is especially affected by dioxins, a group of persistent environmental pollutants, resulting in irreversible abnormalities including effects on sexual function and fertility in adult males and possibly on the development of male offspring. The reproductive toxicity caused by dioxins is mostly mediated by an aryl hydrocarbon receptor (AhR). In animals, spermatogenesis is a highly sensitive and dynamic process that includes proliferation and maturation of germ cells. Spermatogenesis is subject to multiple endogenous and exogenous regulatory factors, including a wide range of environmental toxicants such as dioxins. This review discusses the toxicological effects of dioxins on spermatogenesis and their relevance to male infertility. After a detailed categorization of the environmental contaminants affecting the spermatogenesis, the exposure pathways and bioavailability of dioxins in animals was briefly reviewed. The effects of dioxins on spermatogenesis are then outlined in detail. The endocrine-disrupting effects of dioxins in animals and humans are discussed with a particular focus on their effects on the expression of spermatogenesis-related genes. Finally, the impacts of dioxins on the ratio of X and Y chromosomes, the status of serum sex hormones, the quality and fertility of sperm, and the transgenerational effects of dioxins on male reproduction are reviewed.
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Affiliation(s)
- Walaa Faiad
- Department of Animal Biology, Faculty of Sciences, University of Damascus, Damascus, Syria
| | - Chadi Soukkarieh
- Department of Animal Biology, Faculty of Sciences, University of Damascus, Damascus, Syria
| | - Denis J. Murphy
- School of Applied Sciences, University of South Wales, Wales, United Kingdom
| | - Abdulsamie Hanano
- Department of Molecular Biology and Biotechnology, Atomic Energy Commission of Syria (AECS), Damascus, Syria,Correspondence: Abdulsamie Hanano
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Kohno T, Kojima T. Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells. Cancers (Basel) 2022; 14:cancers14205056. [PMID: 36291839 PMCID: PMC9599675 DOI: 10.3390/cancers14205056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/01/2022] [Accepted: 10/13/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary A novel type of macropinocytosis has been identified as a trigger for the malignant progression of endometrial cancer. Transiently reducing epithelial barrier homeostasis leads to macropinocytosis by splitting between adjacent cells in endometrioid endometrial cancer. Macropinocytosis causes morphological changes in well-differentiated to poorly differentiated cancer cells. Inhibition of macropinocytosis promotes a persistent dormant state in the intrinsic KRAS-mutated cancer cell line Sawano. This review focuses on the mechanisms of atypical macropinocytosis and its effects on cellular function, and it describes the physiological processes involved in inducing resting conditions in endometrioid endometrial cancer cells. Abstract Macropinocytosis is an essential mechanism for the non-specific uptake of extracellular fluids and solutes. In recent years, additional functions have been identified in macropinocytosis, such as the intracellular introduction pathway of drugs, bacterial and viral infection pathways, and nutritional supplement pathway of cancer cells. However, little is known about the changes in cell function after macropinocytosis. Recently, it has been reported that macropinocytosis is essential for endometrial cancer cells to initiate malignant progression in a dormant state. Macropinocytosis is formed by a temporary split of adjacent bicellular junctions of epithelial sheets, rather than from the apical surface or basal membrane, as a result of the transient reduction of tight junction homeostasis. This novel type of macropinocytosis has been suggested to be associated with the malignant pathology of endometriosis and endometrioid endometrial carcinoma. This review outlines the induction of malignant progression of endometrial cancer cells by macropinocytosis based on a new mechanism and the potential preventive mechanism of its malignant progression.
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Zejc T, Piontek J, Schulzke JD, Fromm M, Ervens J, Rosenthal R. Clinical Significance of Claudin Expression in Oral Squamous Cell Carcinoma. Int J Mol Sci 2022; 23:ijms231911234. [PMID: 36232536 PMCID: PMC9569574 DOI: 10.3390/ijms231911234] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 12/24/2022] Open
Abstract
A change in claudin expression has been demonstrated in various tumors. The present study specifically compares claudin expression in oral squamous cell carcinoma (OSCC) with healthy oral epithelium from the same individual and analyzes the association between claudin expression and the clinically relevant course parameters. Our study includes tissue samples and clinically relevant follow-up data from 60 patients with primary and untreated OSCC. The oral mucosa was analyzed via Western blot for the expression of claudin-1, -2, -3, -4, -5, and -7. Importantly, the tumor and healthy tissues were obtained pairwise from patients, allowing for intraindividual comparisons. Both the healthy and tumor epithelium from the oral cavity did not express the claudin-3 protein. The intraindividual comparison revealed that, in OSCC, claudin-2 expression was higher, and the expression of claudin-4, -5, and -7 was lower than in healthy epithelium. An association was found between increased claudin-2 expression and shorter relapse-free survival. In addition, the reduced expression of claudin-4 had a negative impact on relapse-free survival. Furthermore, associations between the reduced expression of claudin-7 and the stage of a tumor, or the presence of lymph node metastases, were found. Thus, the expression level of claudin-2, -4, and -7 appears to be predictive of the diagnosis and prognosis of OSCC.
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Affiliation(s)
- Tatjana Zejc
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Jörg Piontek
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Jörg-Dieter Schulzke
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Michael Fromm
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Jürgen Ervens
- Klinik für HNO-Heilkunde, Kopf- und Halschirurgie, Plastische Chirurgie, Vivantes Klinikum Neukölln, Rudower Straße 48, Neukölln, 12351 Berlin, Germany
| | - Rita Rosenthal
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
- Correspondence: ; Tel.: +49-30-450-514-527
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Ganieva U, Schneiderman S, Bu P, Beaman K, Dambaeva S. IL-22 regulates endometrial regeneration by enhancing tight junctions and orchestrating extracellular matrix. Front Immunol 2022; 13:955576. [PMID: 36091010 PMCID: PMC9453595 DOI: 10.3389/fimmu.2022.955576] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022] Open
Abstract
The uterine endometrium uniquely regenerates after menses, postpartum, or after breaks in the uterine layer integrity throughout women’s lives. Direct cell–cell contacts ensured by tight and adherens junctions play an important role in endometrial integrity. Any changes in these junctions can alter the endometrial permeability of the uterus and have an impact on the regeneration of uterine layers. Interleukin 22 (IL-22) is a cytokine that is recognized for its role in epithelial regeneration. Moreover, it is crucial in controlling the inflammatory response in mucosal tissues. Here, we studied the role of IL-22 in endometrial recovery after inflammation-triggered abortion. Fecundity of mice was studied in consecutive matings of the same animals after lipopolysaccharide (LPS) (10 µg per mouse)-triggered abortion. The fecundity rate after the second mating was substantially different between IL-22 knockout (IL-22−/−) (9.1%) and wild-type (WT) (71.4%) mice (p < 0.05), while there was no difference between the groups in the initial mating, suggesting that IL-22 deficiency might be associated with secondary infertility. A considerable difference was observed between IL-22−/− and WT mice in the uterine clearance following LPS-triggered abortion. Gross examination of the uteri of IL-22−/− mice revealed non-viable fetuses retained inside the horns (delayed clearance). In contrast, all WT mice had completed abortion with total clearance after LPS exposure. We also discovered that IL-22 deficiency is associated with a decreased expression of tight junctions (claudin-2 and claudin-10) and cell surface pathogen protectors (mucin-1). Moreover, IL-22 has a role in the remodeling of the uterine tissue in the inflammatory environment by regulating epithelial–mesenchymal transition markers called E- and N-cadherin. Therefore, IL-22 contributes to the proper regeneration of endometrial layers after inflammation-triggered abortion. Thus, it might have a practical significance to be utilized as a treatment option postpartum (enhanced regeneration function) and in secondary infertility caused by inflammation (enhanced barrier/protector function).
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Affiliation(s)
- Umida Ganieva
- Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Sylvia Schneiderman
- Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Pengli Bu
- Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Kenneth Beaman
- Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Svetlana Dambaeva
- Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- *Correspondence: Svetlana Dambaeva,
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Imakawa K, Kusama K, Kaneko-Ishino T, Nakagawa S, Kitao K, Miyazawa T, Ishino F. Endogenous Retroviruses and Placental Evolution, Development, and Diversity. Cells 2022; 11:cells11152458. [PMID: 35954303 PMCID: PMC9367772 DOI: 10.3390/cells11152458] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
The main roles of placentas include physical protection, nutrient and oxygen import, export of gasses and fetal waste products, and endocrinological regulation. In addition to physical protection of the fetus, the placentas must provide immune protection throughout gestation. These basic functions are well-conserved; however, placentas are undoubtedly recent evolving organs with structural and cellular diversities. These differences have been explained for the last two decades through co-opting genes and gene control elements derived from transposable elements, including endogenous retroviruses (ERVs). However, the differences in placental structures have not been explained or characterized. This manuscript addresses the sorting of ERVs and their integration into the mammalian genomes and provides new ways to explain why placental structures have diverged.
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Affiliation(s)
- Kazuhiko Imakawa
- Research Institute of Agriculture, Tokai University, Kumamoto 862-8652, Japan
- Correspondence: ; Tel.: +81-96-386-2652
| | - Kazuya Kusama
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
| | | | - So Nakagawa
- Department of Molecular Life Science, Tokai University School of Medicine, Nakagawa 259-1193, Japan
| | - Koichi Kitao
- Laboratory of Virus-Host Coevolution, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Takayuki Miyazawa
- Laboratory of Virus-Host Coevolution, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Fumitoshi Ishino
- Institute of Research, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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Sastri KT, Gupta NV, M S, Chakraborty S, Kumar H, Chand P, Balamuralidhara V, Gowda D. Nanocarrier facilitated drug delivery to the brain through intranasal route: A promising approach to transcend bio-obstacles and alleviate neurodegenerative conditions. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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EGF-Dependent Activation of ELK1 Contributes to the Induction of CLDND1 Expression Involved in Tight Junction Formation. Biomedicines 2022; 10:biomedicines10081792. [PMID: 35892692 PMCID: PMC9329870 DOI: 10.3390/biomedicines10081792] [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: 03/21/2022] [Revised: 07/14/2022] [Accepted: 07/22/2022] [Indexed: 11/23/2022] Open
Abstract
Claudin proteins are intercellular adhesion molecules. Increased claudin domain-containing 1 (CLDND1) expression is associated with the malignant transformation of estrogen receptor-negative breast cancer cells with low sensitivity to hormone therapy. Abnormal CLDND1 expression is also implicated in vascular diseases. Previously, we investigated the regulatory mechanism underlying CLDND1 expression and identified a strong enhancer region near the promoter. In silico analysis of the sequence showed high homology to the ETS domain-containing protein-1 (ELK1)-binding sequence which is involved in cell growth, differentiation, angiogenesis, and cancer. Transcriptional ELK1 activation is associated with the mitogen-activated protein kinase (MAPK) signaling cascade originating from the epidermal growth factor receptor (EGFR). Here, we evaluated the effect of gefitinib, an EGFR tyrosine kinase inhibitor, on the suppression of CLDND1 expression using ELK1 overexpression in luciferase reporter and chromatin immunoprecipitation assays. ELK1 was found to be an activator of the enhancer region, and its transient expression increased that of CLDND1 at the mRNA and protein levels. CLDND1 expression was increased following EGF-induced ELK1 phosphorylation. Furthermore, this increase in CLDND1 was significantly suppressed by gefitinib. Therefore, EGF-dependent activation of ELK1 contributes to the induction of CLDND1 expression. These findings open avenues for the development of new anticancer agents targeting CLDND1.
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36
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Saito K, Konno T, Kohno T, Shimada H, Matsuura M, Okada T, Kura A, Ishii D, Kondoh M, Saito T, Kojima T. LSR antibody promotes apoptosis and disrupts epithelial barriers via signal pathways in endometrial cancer. Tissue Barriers 2022:2106113. [PMID: 35883247 PMCID: PMC10364657 DOI: 10.1080/21688370.2022.2106113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Lipolysis-stimulated lipoprotein receptor (LSR), a lipid metabolism-related factor localized in tricellular tight junctions (tTJs), plays an important role in maintaining the epithelial barrier. LSR is highly expressed in well-differentiated endometrial endometrioid carcinoma (EEC), and its expression decreases during malignancy. Angubindin-1, a novel LSR ligand peptide, regulates tTJs without cytotoxicity, enhances paracellular permeability, and regulates epithelial barrier via c-Jun N-terminal kinase (JNK)/cofilin. In this study, we investigated the immune-modulatory roles of an anti-LSR antibody in the treatment of EEC in vitro compared to those of angubindin-1. We prepared an antibody against the extracellular N-terminal domain of human LSR (LSR-N-ab) and angubindin-1. EEC cell-line Sawano cells in 2D and 2.5D cultures were treated with 100 μg/ml LSR-N-ab or 2.5 μg/ml angubindin-1 with or without protein tyrosine kinase 2β inhibitor PF431396 (PF43) and JNK inhibitor SP600125 (SP60) at 10 μM. Treatment with LSR-N-ab and angubindin-1 decreased LSR at the membranes of tTJs and the activity of phosphorylated LSR and phosphorylated cofilin in 2D culture. Treatment with LSR-N-ab and angubindin-1 decreased the epithelial barrier measured as TEER values in 2D culture and enhanced the epithelial permeability of FD-4 in 2.5D culture. Treatment with LSR-N-ab, but not angubindin-1, induced apoptosis in 2D culture. Pretreatment with PF43 and SP60 prevented all the changes induced by treatment with LSR-N-ab and angubindin-1. Treatment with LSR-N-ab and angubindin-1 enhanced the cell metabolism measured as the mitochondrial respiration levels in 2D culture. LSR-N-ab and angubindin-1 may be useful for therapy of human EEC via enhanced apoptosis or drug absorption.
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Affiliation(s)
- Kimihito Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takumi Konno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Kohno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Shimada
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Motoki Matsuura
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tadahi Okada
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Arisa Kura
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Daichi Ishii
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masuo Kondoh
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Tsuyoshi Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takashi Kojima
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Ko YK, Hong S, Kim HM, Liu M, Moon E, Kim P, Choi Y. Characterization of junctional structures in the gingival epithelium as barriers against bacterial invasion. J Periodontal Res 2022; 57:799-810. [PMID: 35607865 DOI: 10.1111/jre.13003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/14/2022] [Accepted: 04/29/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND OBJECTIVE Adherens junctions (AJs) and tight junctions (TJs) are known to play a crucial role in maintaining the physical barrier function of the epithelium. Here, we aimed to characterize the distribution of AJs and TJs throughout the gingival epithelium and to obtain insights into the physiological importance of these junctional structures. METHODS Sections of mouse gingival tissue were examined using transmission electron microscopy (TEM) and bio-high voltage electron microscopy tomography. The gingival sections were stained for E-cadherin and JAM-A as markers of AJs and TJs, respectively, and examined using confocal microscopy and lattice structured illumination microscopy. Bacteria within the gingival epithelium were examined using in situ hybridization. RESULTS Junctional structures, including desmosomes, AJs, and TJs, were observed throughout the gingival epithelium. The expression levels of E-cadherin were particularly low in the granular/keratinized layers of the oral epithelium (OE), while extremely low JAM-A levels were detected in the granular/keratinized layers of the sulcular epithelium (SE). The three-dimensional rendering of the junctional structures revealed that both AJs and TJs in the gingival epithelium formed discontinuous short bands or patches. Interestingly, strong bacterial signals were observed at the granular/keratinized layers of both SE and OE, but a few bacteria were detected within the junctional epithelium (JE) and the basal/spinous layers of the SE and OE. CONCLUSIONS AJs and TJs form a discontinuous barrier throughout paracellular passage in the gingival epithelium; nevertheless, they seem to play an important role in defending against invading bacteria.
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Affiliation(s)
- Yeon Kyeong Ko
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Sujung Hong
- Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.,KI for Health Science and Technology (KIHST), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Hyun Man Kim
- Department of Oral Histology and Developmental Biology, Program of Cell and Developmental Biology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Mengmeng Liu
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Eunyoung Moon
- Electron Microscopy Research Center, Korea Basic Science Institute (KBSI), Daejeon, Korea
| | - Pilhan Kim
- Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.,KI for Health Science and Technology (KIHST), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
| | - Youngnim Choi
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
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Ito Y, Takasawa A, Takasawa K, Murakami T, Akimoto T, Kyuno D, Kawata Y, Shano K, Kirisawa K, Ota M, Aoyama T, Murata M, Sugimoto K, Chiba H, Saito T, Osanai M. Aberrant expression of claudin-6 contributes to malignant potentials and drug resistance of cervical adenocarcinoma. Cancer Sci 2022; 113:1519-1530. [PMID: 35100472 PMCID: PMC8990859 DOI: 10.1111/cas.15284] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/09/2022] [Accepted: 01/24/2022] [Indexed: 11/30/2022] Open
Abstract
Recent studies have revealed that aberrant expression of tight junction (TJ) proteins is a hallmark of various solid tumors and it is recognized as a useful therapeutic target. Claudin‐6 (CLDN6), a member of the family of TJ transmembrane proteins, is an ideal therapeutic target because it is not expressed in human adult normal tissues. In this study, we found that CLDN6 is highly expressed in uterine cervical adenocarcinoma (ADC) and that high CLDN6 expression was correlated with lymph node metastasis and lymphovascular infiltration and was an independent prognostic factor. Shotgun proteome analysis revealed that cell‐cell adhesion‐related proteins and drug metabolism‐associated proteins (aldo‐keto reductase [AKR] family proteins) were significantly increased in CLDN6‐overexpressing cells. Furthermore, overexpression of CLDN6 enhanced cell‐cell adhesion properties and attenuated sensitivity to anticancer drugs including doxorubicin, daunorubicin, and cisplatin. Taken together, the results indicate that aberrant expression of CLDN6 enhances malignant potentials and drug resistance of cervical ADC, possibly due to increased cell‐cell adhesion properties and drug metabolism. Our findings provide an insight into a new therapeutic strategy, a CLDN6‐targeting therapy, against cervical ADC.
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Affiliation(s)
- Yui Ito
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Taro Murakami
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Taishi Akimoto
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Daisuke Kyuno
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Yuka Kawata
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Kodai Shano
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Kurara Kirisawa
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Misaki Ota
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Kotaro Sugimoto
- Department of Basic Pathology, Graduate School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan
| | - Hideki Chiba
- Department of Basic Pathology, Graduate School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan
| | - Tsuyoshi Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo, 060-8556, Japan
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Ma Y, Wang C, Elmhadi M, Zhang H, Liu F, Gao X, Wang H. Dietary supplementation of thiamine enhances colonic integrity and modulates mucosal inflammation injury in goats challenged by lipopolysaccharide and low pH. Br J Nutr 2022; 128:1-11. [PMID: 35057872 DOI: 10.1017/s0007114522000174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The current study aimed to investigate the protective effects of dietary thiamine supplementation on the regulation of colonic integrity and mucosal inflammation in goats fed a high-concentrate (HC) diet. Twenty-four Boer goats (live weight of 35·62 (sem 2·4) kg) were allocated to three groups (CON: concentrate/forage = 30:70; HC; concentrate/forage = 70:30 and HCT: concentrate/forage = 70:30 with 200 mg thiamine/kg DMI) for 12 weeks. Results showed that compared with the HC treatment, the HCT group had a significantly higher ruminal pH value from 0 to 12 h after the feeding. The haematoxylin-eosin staining showed that desquamation and severe cellular damage were observed in the colon epithelium of the HC group, whereas the HCT group exhibited more structural integrity of the epithelial cell morphology. Compared with the HC treatment, the HCT group showed a markedly increase in pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes activity. The mRNA expressions in the colonic epithelium of SLC19A2, SLC19A3, SLC25A19, Bcl-2, occludin, claudin-1, claudin-4 and ZO-1 in the HCT group were significantly increased in comparison with the HC diet treatment. Compared with the HC treatment, the HCT diet significantly increased the protein expression of claudin-1 and significantly decreased the protein expression of NF-κB-related proteins p65. The results show that dietary thiamine supplementation could improve the colon epithelial barrier function and alleviate mucosal inflammation injury in goats after lipopolysaccharide and low pH challenge.
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Affiliation(s)
- Yi Ma
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
- Queen Elizabeth II Medical Centre, School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Chao Wang
- Queen Elizabeth II Medical Centre, School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Mawda Elmhadi
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
| | - Hao Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
| | - Fuyuan Liu
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, People's Republic of China
| | - Xingliang Gao
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, People's Republic of China
| | - Hongrong Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
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Tang J, Cai L, Xu C, Sun S, Liu Y, Rosenecker J, Guan S. Nanotechnologies in Delivery of DNA and mRNA Vaccines to the Nasal and Pulmonary Mucosa. NANOMATERIALS 2022; 12:nano12020226. [PMID: 35055244 PMCID: PMC8777913 DOI: 10.3390/nano12020226] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/03/2022] [Accepted: 01/05/2022] [Indexed: 02/07/2023]
Abstract
Recent advancements in the field of in vitro transcribed mRNA (IVT-mRNA) vaccination have attracted considerable attention to such vaccination as a cutting-edge technique against infectious diseases including COVID-19 caused by SARS-CoV-2. While numerous pathogens infect the host through the respiratory mucosa, conventional parenterally administered vaccines are unable to induce protective immunity at mucosal surfaces. Mucosal immunization enables the induction of both mucosal and systemic immunity, efficiently removing pathogens from the mucosa before an infection occurs. Although respiratory mucosal vaccination is highly appealing, successful nasal or pulmonary delivery of nucleic acid-based vaccines is challenging because of several physical and biological barriers at the airway mucosal site, such as a variety of protective enzymes and mucociliary clearance, which remove exogenously inhaled substances. Hence, advanced nanotechnologies enabling delivery of DNA and IVT-mRNA to the nasal and pulmonary mucosa are urgently needed. Ideal nanocarriers for nucleic acid vaccines should be able to efficiently load and protect genetic payloads, overcome physical and biological barriers at the airway mucosal site, facilitate transfection in targeted epithelial or antigen-presenting cells, and incorporate adjuvants. In this review, we discuss recent developments in nucleic acid delivery systems that target airway mucosa for vaccination purposes.
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Affiliation(s)
- Jie Tang
- Department of Pediatrics, Ludwig-Maximilians University of Munich, 80337 Munich, Germany;
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, Australia;
| | - Larry Cai
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, Australia;
| | - Chuanfei Xu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Third Military Medical University, Chongqing 400038, China; (C.X.); (S.S.); (Y.L.)
| | - Si Sun
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Third Military Medical University, Chongqing 400038, China; (C.X.); (S.S.); (Y.L.)
| | - Yuheng Liu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Third Military Medical University, Chongqing 400038, China; (C.X.); (S.S.); (Y.L.)
| | - Joseph Rosenecker
- Department of Pediatrics, Ludwig-Maximilians University of Munich, 80337 Munich, Germany;
- Correspondence: (J.R.); (S.G.); Tel.: +49-89-440057713 (J.R.); +86-23-68771645 (S.G.)
| | - Shan Guan
- Department of Pediatrics, Ludwig-Maximilians University of Munich, 80337 Munich, Germany;
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Third Military Medical University, Chongqing 400038, China; (C.X.); (S.S.); (Y.L.)
- Correspondence: (J.R.); (S.G.); Tel.: +49-89-440057713 (J.R.); +86-23-68771645 (S.G.)
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Wei LY, Zhang JK, Zheng L, Chen Y. The functional role of sulforaphane in intestinal inflammation: a review. Food Funct 2021; 13:514-529. [PMID: 34935814 DOI: 10.1039/d1fo03398k] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Intestinal inflammation represented by inflammatory bowel disease (IBD) has become a global epidemic disease and the number of patients with IBD continues to increase. This digestive tract disease not only affects the absorption of food components by destroying the intestinal epithelial structure, but also can induce diseases in remote organs via the gut-organ axis, seriously harming human health. Nowadays, increasing attention is being paid to the nutritional and medicinal value of food components with increasing awareness among the general public regarding health. As an important member of the isothiocyanates, sulforaphane (SFN) is abundant in cruciferous plants and is famous for its excellent anti-cancer effects. With the development of clinical research, more physiological activities of SFN, such as antidepressant, hypoglycemic and anti-inflammatory activities, have been discovered, supporting the fact that SFN and SFN-rich sources have great potential to be dietary supplements that are beneficial to health. This review summarizes the characteristics of intestinal inflammation, the anti-inflammatory mechanism of SFN and its various protective effects on intestinal inflammation, and the possible future applications of SFN for promoting intestinal health have also been discussed.
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Affiliation(s)
- Li-Yang Wei
- Chinese Academy of Inspection and Quarantine, Beijing, 100176, People's Republic of China. .,School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China.
| | - Jiu-Kai Zhang
- Chinese Academy of Inspection and Quarantine, Beijing, 100176, People's Republic of China.
| | - Lei Zheng
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China.
| | - Ying Chen
- Chinese Academy of Inspection and Quarantine, Beijing, 100176, People's Republic of China.
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Shimada H, Kohno T, Konno T, Okada T, Saito K, Shindo Y, Kikuchi S, Tsujiwaki M, Ogawa M, Matsuura M, Saito T, Kojima T. The Roles of Tricellular Tight Junction Protein Angulin-1/Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Endometriosis and Endometrioid-Endometrial Carcinoma. Cancers (Basel) 2021; 13:6341. [PMID: 34944960 PMCID: PMC8699113 DOI: 10.3390/cancers13246341] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/04/2021] [Accepted: 12/05/2021] [Indexed: 12/11/2022] Open
Abstract
Tight junction proteins play roles beyond permeability barriers functions and control cell proliferation and differentiation. The relation between tight junctions and the signal transduction pathways affects cell growth, invasion and migration. Abnormality of tight junction proteins closely contributes to epithelial mesenchymal transition (EMT) and malignancy of various cancers. Angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) forms tricellular contacts that has a barrier function. Downregulation of angulin-1/LSR correlates with the malignancy in various cancers, including endometrioid-endometrial carcinoma (EEC). These alterations have been shown to link to not only multiple signaling pathways such as Hippo/YAP, HDAC, AMPK, but also cell metabolism in ECC cell line Sawano. Moreover, loss of angulin-1/LSR upregulates claudin-1, and loss of apoptosis stimulating p53 protein 2 (ASPP2) downregulates angulin-1/LSR. Angulin-1/LSR and ASPP2 concentrate at both midbody and centrosome in cytokinesis. In EEC tissues, angulin-1/LSR and ASPP2 are reduced and claudin-2 is overexpressed during malignancy, while in the tissues of endometriosis changes in localization of angulin-1/LSR and claudin-2 are seen. This review highlights how downregulation of angulin-1/LSR promotes development of endometriosis and EEC and discusses about the roles of angulin-1/LSR and its related proteins, including claudins and ASPP2.
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Affiliation(s)
- Hiroshi Shimada
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (H.S.); (T.K.); (T.O.); (K.S.); (Y.S.)
- Departments of Obstetrics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (M.O.); (M.M.); (T.S.)
| | - Takayuki Kohno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (H.S.); (T.K.); (T.O.); (K.S.); (Y.S.)
| | - Takumi Konno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (H.S.); (T.K.); (T.O.); (K.S.); (Y.S.)
| | - Tadahi Okada
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (H.S.); (T.K.); (T.O.); (K.S.); (Y.S.)
- Departments of Obstetrics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (M.O.); (M.M.); (T.S.)
| | - Kimihito Saito
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (H.S.); (T.K.); (T.O.); (K.S.); (Y.S.)
- Departments of Obstetrics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (M.O.); (M.M.); (T.S.)
| | - Yuma Shindo
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (H.S.); (T.K.); (T.O.); (K.S.); (Y.S.)
| | - Shin Kikuchi
- Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan;
| | - Mitsuhiro Tsujiwaki
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan;
| | - Marie Ogawa
- Departments of Obstetrics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (M.O.); (M.M.); (T.S.)
| | - Motoki Matsuura
- Departments of Obstetrics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (M.O.); (M.M.); (T.S.)
| | - Tsuyoshi Saito
- Departments of Obstetrics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (M.O.); (M.M.); (T.S.)
| | - Takashi Kojima
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (H.S.); (T.K.); (T.O.); (K.S.); (Y.S.)
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Qu H, Jin Q, Quan C. CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers. Int J Mol Sci 2021; 22:ijms222413416. [PMID: 34948213 PMCID: PMC8705207 DOI: 10.3390/ijms222413416] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/06/2021] [Accepted: 12/12/2021] [Indexed: 02/07/2023] Open
Abstract
Claudins (CLDNs) are the most important tight junction proteins, which are mainly expressed in endothelial cells or epithelial cells in a tissue-specific manner. As a member of the CLDNs family, CLDN6 is highly expressed in fetal tissues such as the stomach, pancreas, lung, and kidney, but is not expressed in corresponding adult tissues. The expression of CLDN6 is regulated by a variety of factors, including but not limited to stimuli and transcription factors, DNA methylation, and post-translational modifications. CLDN6 has been found to have a key role in the formation of barriers, especially the lung epithelial barrier and the epidermal permeability barrier (EPB). Importantly, the roles of CLDN6 in cancers have gained focus and are being investigated in recent years. Strong evidence indicates that the altered expression of CLDN6 is linked to the development of various cancers. Malignant phenotypes of tumors affected by CLDN6 include proliferation and apoptosis, migration and invasion, and drug resistance, which are regulated by CLDN6-mediated key signaling pathways. Given the important role in tumors and its low or no expression in normal tissues, CLDN6 is an ideal target for tumor therapy. This review aims to provide an overview of the structure and regulation of CLDN6, and its traditional barrier function, with a special emphasis on its emerging roles in cancers, including its impact on the malignant phenotypes, signal-modulating effects, the prognosis of tumor patients, and clinical applications in cancers.
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Phattarataratip E, Sappayatosok K. Differential Expression of Claudin in Odontogenic Cysts. Eur J Dent 2021; 16:320-326. [PMID: 34808689 PMCID: PMC9339929 DOI: 10.1055/s-0041-1740440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Objective
This study aimed to analyze claudin-1, -4, and -7 expression in different types of odontogenic cysts (odontogenic keratocysts [OKCs], dentigerous cysts [DCs], calcifying odontogenic cysts [COCs], and radicular cysts [RCs]) as well as its association with OKC recurrence.
Materials and Methods
Seventy samples of odontogenic cysts samples were immunohistochemically stained to detect claudin-1, -4, and -7 expression. Patient information and OKC recurrence data were recorded. The staining was analyzed semiquantitatively and categorized based on the pattern and percentage of positively stained cystic epithelial cells.
Statistical Analysis
Expression of different claudins between groups was analyzed using the Kruskal–Wallis test with Dunn's test, followed by post hoc pairwise comparison. The association between claudin expression and OKC recurrence was analyzed by the Mann–Whitney U test. Correlations among claudin expression were examined with Spearman's correlation coefficient. Level of significance was at
p
< 0.005.
Results
Claudin-1 was widely expressed in every odontogenic cyst. Most DCs (50%) expressed claudin-1 in more than 75% of cells, as did RCs (65%), while most OKCs (50%) expressed claudin-1 in 26 to 50% of cells. Most COCs (50%) expressed claudin-1 in 51 to 75% of cells. Every sample of OKC and RC was positive for claudin-4, but no sample showed staining in more than 51% of cells. Every odontogenic cyst was positive for claudin-7. DCs (35%), OKCs (55%), and RCs (40%) mostly showed staining in 26 to 50% of cells. High claudin-1 expression was shown in COCs, DCs, and RCs, while low expression of claudin-4 was shown in every odontogenic cyst. For claudin-7, the expression is high only in COCs. Claudin-1 and -4 was significantly different among each odontogenic cyst. High expression of claudin-1 was correlated with OKC recurrence. The correlations of claudin-1 with claudin-7 expression and claudin-4 with claudin-7 expression were significant in DCs. In COCs, claudin-1 and claudin-7 expression was significantly correlated.
Conclusions
The expression of claudin-1, -4, and -7 was present in every odontogenic cyst, but the proportion of positive staining cells was different. Expression of claudin-1 is associated with OKC recurrence. Dysregulation of claudin expression may play a pathogenic role in cyst pathogenesis.
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Affiliation(s)
- Ekarat Phattarataratip
- Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Kraisorn Sappayatosok
- Department of Oral Diagnostic Sciences, College of Dental Medicine, Rangsit University, Pathum Thani, Thailand
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45
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Massa HM, Spann KM, Cripps AW. Innate Immunity in the Middle Ear Mucosa. Front Cell Infect Microbiol 2021; 11:764772. [PMID: 34778109 PMCID: PMC8586084 DOI: 10.3389/fcimb.2021.764772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/11/2021] [Indexed: 01/14/2023] Open
Abstract
Otitis media (OM) encompasses a spectrum of clinical presentations ranging from the readily identifiable Acute OM (AOM), which is characterised by otalgia and fever, to chronic otitis media with effusion (COME) where impaired hearing due to middle ear effusion may be the only clinical symptom. Chronic suppurative OM (CSOM) presents as a more severe form of OM, involving perforation of the tympanic membrane. The pathogenesis of OM in these varied clinical presentations is unclear but activation of the innate inflammatory responses to viral and/or bacterial infection of the upper respiratory tract performs an integral role. This localised inflammatory response can persist even after pathogens are cleared from the middle ear, eustachian tubes and, in the case of respiratory viruses, even the nasal compartment. Children prone to OM may experience an over exuberant inflammatory response that underlies the development of chronic forms of OM and their sequelae, including hearing impairment. Treatments for chronic effusive forms of OM are limited, with current therapeutic guidelines recommending a "watch and wait" strategy rather than active treatment with antibiotics, corticosteroids or other anti-inflammatory drugs. Overall, there is a clear need for more targeted and effective treatments that either prevent or reduce the hyper-inflammatory response associated with chronic forms of OM. Improved treatment options rely upon an in-depth understanding of OM pathogenesis, particularly the role of the host innate immune response during acute OM. In this paper, we review the current literature regarding the innate immune response within the middle ear to bacterial and viral otopathogens alone, and as co-infections. This is an important consideration, as the role of respiratory viruses as primary pathogens in OM is not yet fully understood. Furthermore, increased reporting from PCR-based diagnostics, indicates that viral/bacterial co-infections in the middle ear are more common than bacterial infections alone. Increasingly, the mechanisms by which viral/bacterial co-infections may drive or maintain complex innate immune responses and inflammation during OM as a chronic response require investigation. Improved understanding of the pathogenesis of chronic OM, including host innate immune response within the middle ear is vital for development of improved diagnostic and treatment options for our children.
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Affiliation(s)
- Helen M Massa
- School of Pharmacy and Medical Science, Griffith University, Gold Coast, QLD, Australia
| | - Kirsten M Spann
- Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Allan W Cripps
- Menzies Health Institute Queensland, School of Medicine, Griffith University, Gold Coast, QLD, Australia.,School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia
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Upadhaya P, Giri S, Barhoi D, Bhattacharjee A. Altered expression of junctional proteins as a potential biomarker in oral precancerous and cancerous patients. Tissue Barriers 2021; 10:1973329. [PMID: 34534039 DOI: 10.1080/21688370.2021.1973329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Due to a lower survival rate in patients with advanced clinical stages of oral cancer, discovering a biomarker that could diagnose and predict disease progression is vital. Cell-cell junctional proteins play a crucial role in the maintenance of tissue architecture but are often deregulated in different cancer. The present study investigates the expression of cell-cell junctional proteins viz: e-cadherin (E-cad) and zonula occludens-1 (ZO-1) in oral precancerous (OED) and cancerous (OSCC) patients to monitor if they can serve as practicable molecular markers. The ultrastructural junctional complex was studied by transmission electron microscopy, and the expression of proteins was performed by immunohistochemistry. The relationship between the expression of protein and clinicopathological features of the patients was checked by Pearson's correlation test. Furthermore, the survival curve of the follow-up data was estimated by the Kaplan-Meier method. We observed a disrupted junctional complex and a significantly decreased immunoexpression of E-cad and ZO-1 in OED and OSCC when compared to the adjacent non-cancerous tissues. The expression of ZO-1 was associated with TNM stages, whereas E-cad was associated with histological grades as well as TNM stages. A positive correlation was observed between the expression of ZO-1 and E-cad proteins in OED and OSCC. Further, follow-up studies revealed that high ZO-1 and E-cad expressing patients survived longer than their low expressed counterparts. The present study shows disruption of junctional complex and alteration of junctional proteins expression that could draw the attention of health professionals to explore junctional proteins as a possible therapeutic target in oral cancer.
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Affiliation(s)
- Puja Upadhaya
- Laboratory of Molecular and Cell Biology, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Sarbani Giri
- Laboratory of Molecular and Cell Biology, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Dharmeswar Barhoi
- Laboratory of Molecular and Cell Biology, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
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Ji W, Hu Q, Zhang M, Zhang C, Chen C, Yan Y, Zhang X, Chen S, Tao L, Zhang W, Jin Y, Duan G. The Disruption of the Endothelial Barrier Contributes to Acute Lung Injury Induced by Coxsackievirus A2 Infection in Mice. Int J Mol Sci 2021; 22:9895. [PMID: 34576058 PMCID: PMC8467819 DOI: 10.3390/ijms22189895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/15/2021] [Accepted: 09/10/2021] [Indexed: 01/10/2023] Open
Abstract
Sporadic occurrences and outbreaks of hand, foot, and mouth disease (HFMD) caused by Coxsackievirus A2 (CVA2) have frequently reported worldwide recently, which pose a great challenge to public health. Epidemiological studies have suggested that the main cause of death in critical patients is pulmonary edema. However, the pathogenesis of this underlying comorbidity remains unclear. In this study, we utilized the 5-day-old BALB/c mouse model of lethal CVA2 infection to evaluate lung damage. We found that the permeability of lung microvascular was significantly increased after CVA2 infection. We also observed the direct infection and apoptosis of lung endothelial cells as well as the destruction of tight junctions between endothelial cells. CVA2 infection led to the degradation of tight junction proteins (e.g., ZO-1, claudin-5, and occludin). The gene transcription levels of von Willebrand factor (vWF), endothelin (ET), thrombomodulin (THBD), granular membrane protein 140 (GMP140), and intercellular cell adhesion molecule-1 (ICAM-1) related to endothelial dysfunction were all significantly increased. Additionally, CVA2 infection induced the increased expression of inflammatory cytokines (IL-6, IL-1β, and MCP-1) and the activation of p38 mitogen-activated protein kinase (MAPK). In conclusion, the disruption of the endothelial barrier contributes to acute lung injury induced by CVA2 infection; targeting p38-MAPK signaling may provide a therapeutic approach for pulmonary edema in critical infections of HFMD.
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Affiliation(s)
- Wangquan Ji
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Qiang Hu
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Mengdi Zhang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Chuwen Zhang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Chen Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Yujie Yan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Xue Zhang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Shuaiyin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Ling Tao
- School of Public Health, Xinxiang Medical University, Xinxiang 453003, China;
| | - Weiguo Zhang
- Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA;
| | - Yuefei Jin
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
| | - Guangcai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; (W.J.); (Q.H.); (M.Z.); (C.Z.); (C.C.); (Y.Y.); (X.Z.); (S.C.)
- Henan Key Laboratory of Molecular Medicine, Zhengzhou University, Zhengzhou 450001, China
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Su X, Wei J, Qi H, Jin M, Zhang Q, Zhang Y, Zhang C, Yang R. LRRC19 Promotes Permeability of the Gut Epithelial Barrier Through Degrading PKC-ζ and PKCι/λ to Reduce Expression of ZO1, ZO3, and Occludin. Inflamm Bowel Dis 2021; 27:1302-1315. [PMID: 33501933 DOI: 10.1093/ibd/izaa354] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND A dysfunctional gut epithelial barrier allows the augmented permeation of endotoxins, luminal antigens, and bacteria into the bloodstream, causing disease. The maintenance of gut epithelial barrier integrity may be regulated by multiple factors. Herein we analyze the role of leucine-rich repeat-containing protein 19 (LRRC19) in regulating the permeability of the gut epithelial barrier. METHODS We utilized Lrrc19 knockout (KO) mice and clinical samples through transmission electron, intestinal permeability assay, Western blot, and immunofluorescence staining to characterize the role of LRRC19 in the permeability of the gut epithelial barrier. RESULTS We found that LRRC19, which is expressed in gut epithelial cells, impairs gut barrier function. Transmission electron micrographs revealed a tighter junction and narrower gaps in the colon epithelium cells in LRRC19 KO mice. There were lower levels of serum lipopolysaccharide and 4 kDa-fluorescein isothiocyanate-dextran after gavage in LRRC19 KO mice than in wild-type mice. We found that LRRC19 could reduce the expression of zonula occludens (ZO)-1, ZO-3, and occludin in the colonic epithelial cells. The decreased expression of ZO-1, ZO-3, and occludin was dependent on degrading protein kinase C (PKC) ζ and PKCι/λ through K48 ubiquitination by LRRC19. The expression of LRRC19 was also negatively correlated with ZO-1, ZO-3, occludin, PKCζ, and PKCι/λ in human colorectal cancers. CONCLUSIONS The protein LRRC19 can promote the permeability of the gut epithelial barrier through degrading PKC ζ and PKCι/λ to reduce the expression of ZO-1, ZO-3, and occludin.
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Affiliation(s)
- Xiaomin Su
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Jianmei Wei
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Houbao Qi
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Mengli Jin
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Qianjing Zhang
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Yuan Zhang
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Rongcun Yang
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
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Tesch F, Siegerist F, Hay E, Artelt N, Daniel C, Amann K, Zimmermann U, Kavvadas P, Grisk O, Chadjichristos C, Endlich K, Chatziantoniou C, Endlich N. Super-resolved local recruitment of CLDN5 to filtration slits implicates a direct relationship with podocyte foot process effacement. J Cell Mol Med 2021; 25:7631-7641. [PMID: 34156149 PMCID: PMC8358871 DOI: 10.1111/jcmm.16519] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 11/28/2022] Open
Abstract
Under healthy conditions, foot processes of neighbouring podocytes are interdigitating and connected by an electron‐dense slit diaphragm. Besides slit diaphragm proteins, typical adherens junction proteins are also found to be expressed at this cell‐cell junction. It is therefore considered as a highly specialized type of adherens junction. During podocyte injury, podocyte foot processes lose their characteristic 3D structure and the filtration slits typical meandering structure gets linearized. It is still under debate how this change of structure leads to the phenomenon of proteinuria. Using super‐resolution 3D‐structured illumination microscopy, we observed a spatially restricted up‐regulation of the tight junction protein claudin‐5 (CLDN5) in areas where podocyte processes of patients suffering from minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) as well as in murine nephrotoxic serum (NTS) nephritis and uninephrectomy DOCA‐salt hypertension models, were locally injured. CLDN5/nephrin ratios in human glomerulopathies and NTS‐treated mice were significantly higher compared to controls. In patients, the CLDN5/nephrin ratio is significantly correlated with the filtration slit density as a foot process effacement marker, confirming a direct association of local CLDN5 up‐regulation in injured foot processes. Moreover, CLDN5 up‐regulation was observed in some areas of high filtration slit density, suggesting that CLND5 up‐regulation preceded the changes of foot processes. Therefore, CLDN5 could serve as a biomarker predicting early foot process effacement.
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Affiliation(s)
- Florian Tesch
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Florian Siegerist
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Eleonora Hay
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.,Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Nadine Artelt
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Christoph Daniel
- Department of Nephropathology, Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Uwe Zimmermann
- Department of Urology, University Medicine Greifswald, Greifswald, Germany
| | | | - Olaf Grisk
- Institute for Physiology, Medizinische Hochschule Brandenburg Theodor Fontane, Neuruppin, Germany
| | | | - Karlhans Endlich
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | | | - Nicole Endlich
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
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Scalise AA, Kakogiannos N, Zanardi F, Iannelli F, Giannotta M. The blood-brain and gut-vascular barriers: from the perspective of claudins. Tissue Barriers 2021; 9:1926190. [PMID: 34152937 PMCID: PMC8489939 DOI: 10.1080/21688370.2021.1926190] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
In some organs, such as the brain, endothelial cells form a robust and highly selective blood-to-tissue barrier. However, in other organs, such as the intestine, endothelial cells provide less stringent permeability, to allow rapid exchange of solutes and nutrients where needed. To maintain the structural and functional integrity of the highly dynamic blood–brain and gut–vascular barriers, endothelial cells form highly specialized cell-cell junctions, known as adherens junctions and tight junctions. Claudins are a family of four-membrane-spanning proteins at tight junctions and they have both barrier-forming and pore-forming properties. Tissue-specific expression of claudins has been linked to different diseases that are characterized by barrier impairment. In this review, we summarize the more recent progress in the field of the claudins, with particular attention to their expression and function in the blood–brain barrier and the recently described gut–vascular barrier, under physiological and pathological conditions. Abbreviations: 22q11DS 22q11 deletion syndrome; ACKR1 atypical chemokine receptor 1; AD Alzheimer disease; AQP aquaporin; ATP adenosine triphosphate; Aβ amyloid β; BAC bacterial artificial chromosome; BBB blood-brain barrier; C/EBP-α CCAAT/enhancer-binding protein α; cAMP cyclic adenosine monophosphate (or 3ʹ,5ʹ-cyclic adenosine monophosphate); CD cluster of differentiation; CNS central nervous system; DSRED discosoma red; EAE experimental autoimmune encephalomyelitis; ECV304 immortalized endothelial cell line established from the vein of an apparently normal human umbilical cord; EGFP enhanced green fluorescent protein; ESAM endothelial cell-selective adhesion molecule; GLUT-1 glucose transporter 1; GVB gut-vascular barrier; H2B histone H2B; HAPP human amyloid precursor protein; HEK human embryonic kidney; JACOP junction-associated coiled coil protein; JAM junctional adhesion molecules; LYVE1 lymphatic vessel endothelial hyaluronan receptor 1; MADCAM1 mucosal vascular addressin cell adhesion molecule 1; MAPK mitogen-activated protein kinase; MCAO middle cerebral artery occlusion; MMP metalloprotease; MS multiple sclerosis; MUPP multi-PDZ domain protein; PATJ PALS-1-associated tight junction protein; PDGFR-α platelet-derived growth factor receptor α polypeptide; PDGFR-β platelet-derived growth factor receptor β polypeptide; RHO rho-associated protein kinase; ROCK rho-associated, coiled-coil-containing protein kinase; RT-qPCR real time quantitative polymerase chain reactions; PDGFR-β soluble platelet-derived growth factor receptor, β polypeptide; T24 human urinary bladder carcinoma cells; TG2576 transgenic mice expressing the human amyloid precursor protein; TNF-α tumor necrosis factor α; WTwild-type; ZO zonula occludens.
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