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Salama A, El-Fadaly AA, Elgohary R. Effect of atorvastatin on lipopolysaccharide-induced lung inflammation and hypoxia in mice; modulation of HIF-1α, CINC and MIP-2. Immunopharmacol Immunotoxicol 2024:1-9. [PMID: 39632508 DOI: 10.1080/08923973.2024.2436089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 11/24/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Acute lung injury is a crucial pathological state, particularly in some severe infectious respiratory illnesses, distinguished by acute inflammation, pulmonary edema, hypoxia, and neutrophil recruitment. Cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) play a vital role in neutrophil recruitment. OBJECTIVE Here, we validated the potential repressing effect of atorvastatin on acute lung injury induced by lipopolysaccharide (LPS) in mice. MATERIALS AND METHODS Mice were injected with LPS (250 μg/kg; i.p.) daily for 7 days, and atorvastatin (25 and 50 mg/kg; orally) daily along with LPS. RESULTS Atorvastatin ameliorated oxidative stress as evidenced by increased reduced glutathione (GSH) and nuclear factor-erythroid 2 related factor 2 (Nrf2) levels and decreased malondialdehyde (MDA) levels. Additionally, it lessened inflammatory biomarkers including tumor necrosis factor-alpha (TNF-α), mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), CINC, and MIP-2, as well as hypoxia biomarker hypoxia-inducible factor-1α (HIF-1α). Moreover, atorvastatin slowed the progression of lung tissue histological lesions. CONCLUSION Collectively, the present study suggests that, atorvastatin effectively protects against LPS-induced acute lung injury through inhibition of oxidative stress, inflammation, hypoxia, and neutrophil recruitment.
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Affiliation(s)
- Abeer Salama
- Department of Pharmacology, National Research Centre, Cairo, Egypt
| | | | - Rania Elgohary
- Department of Narcotics, Ergogenics and Poisons, National Research Centre, Cairo, Egypt
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Yang Y, Zhou X, Deng H, Chen L, Zhang X, Wu S, Song A, Liang F. The role of O-GlcNAcylation in bone metabolic diseases. Front Physiol 2024; 15:1416967. [PMID: 38915778 PMCID: PMC11194333 DOI: 10.3389/fphys.2024.1416967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 05/20/2024] [Indexed: 06/26/2024] Open
Abstract
O-GlcNAcylation, as a post-translational modification, can modulate cellular activities such as kinase activity, transcription-translation, protein degradation, and insulin signaling by affecting the function of the protein substrate, including cellular localization of proteins, protein stability, and protein/protein interactions. Accumulating evidence suggests that dysregulation of O-GlcNAcylation is associated with disease progression such as cancer, neurodegeneration, and diabetes. Recent studies suggest that O-GlcNAcylation is also involved in the regulation of osteoblast, osteoclast and chondrocyte differentiation, which is closely related to the initiation and development of bone metabolic diseases such as osteoporosis, arthritis and osteosarcoma. However, the potential mechanisms by which O-GlcNAcylation regulates bone metabolism are not fully understood. In this paper, the literature related to the regulation of bone metabolism by O-GlcNAcylation was summarized to provide new potential therapeutic strategies for the treatment of orthopedic diseases such as arthritis and osteoporosis.
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Affiliation(s)
- Yajing Yang
- College of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
| | - Xuchang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
- School of Medicine, Xiamen University, Xiamen, China
| | - HuiLi Deng
- School of Medicine, Xiamen University, Xiamen, China
| | - Li Chen
- College of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
- Hubei Shizhen Laboratory, Wuhan, China
- Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Wuhan, China
- University of Chinese Medicine (Hubei Provincial Hospital of Traditional Chinese Medicine), Wuhan, China
| | - Xiaolin Zhang
- College of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
- Hubei Shizhen Laboratory, Wuhan, China
- Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Wuhan, China
- University of Chinese Medicine (Hubei Provincial Hospital of Traditional Chinese Medicine), Wuhan, China
| | - Song Wu
- College of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
- Hubei Shizhen Laboratory, Wuhan, China
- Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Wuhan, China
- University of Chinese Medicine (Hubei Provincial Hospital of Traditional Chinese Medicine), Wuhan, China
| | - Aiqun Song
- College of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
- Hubei Shizhen Laboratory, Wuhan, China
- Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Wuhan, China
- University of Chinese Medicine (Hubei Provincial Hospital of Traditional Chinese Medicine), Wuhan, China
| | - Fengxia Liang
- College of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
- Hubei Shizhen Laboratory, Wuhan, China
- Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Wuhan, China
- University of Chinese Medicine (Hubei Provincial Hospital of Traditional Chinese Medicine), Wuhan, China
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Uyulgan S, Köse SN, Kıpçak A, Başkan Y, Dağlar G, Karagonlar ZF, Yandım C. Thyroid hormone T3 augments the cytotoxicity of sorafenib in Huh7 hepatocellular carcinoma cells by suppressing AKT expression. J Cancer Res Ther 2024; 20:755-762. [PMID: 39023579 DOI: 10.4103/jcrt.jcrt_2106_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 10/19/2022] [Indexed: 07/20/2024]
Abstract
BACKGROUND AND OBJECTIVES Hepatocellular carcinoma (HCC) is a primary cancer that poorly responds to treatment. Molecular cancer studies led to the development of kinase inhibitors, among which sorafenib stands out as a multi-kinase inhibitor approved by FDA for first line use in HCC patients. However, the efficiency of sorafenib was shown to be counteracted by numerous subcellular pathways involving the effector kinase AKT, causing resistance and limiting its survival benefit. On the way of breaking such resistance mechanisms and increase the efficiency of sorafenib, deeper understanding of hepatocellular physiology is essential. Thyroid hormones were shown to be metabolized in liver and inevitably affect the molecular behaviour of hepatocytes. Interestingly, thyroid hormone T3 was also demonstrated to be potentially influential in liver regeneration and treatment with this hormone reportedly led to a decrease in HCC tumor growths. In this study, we aimed to uncover the impact of T3 hormone on the cytotoxic response to sorafenib in HCC in vitro. MATERIALS AND METHODS We pre-treated the HCC cell line Huh-7 with T3 prior to sorafenib exposure both in 2D and 3D culture. We checked cell viability with MTT assay in 2D culture and measured the sizes of 3D spheroids with bright-field microscopy followed by a surface analysis with ImageJ. We also performed scratch assay to measure cell migration as well as western blot and qPCR to uncover affected pathways. RESULTS We observed an additive effect to sorafenib's cytotoxicity both in 2D and 3D culture. Cell migration assay also confirmed our finding and pointed out a benefit of T3 hormone in HCC cell migration. Western blot experiments showed that T3 exerts its additive effect by suppressing AKT expression upon sorafenib treatment both at protein and gene expression levels. CONCLUSION Our results open a promising new avenue in increasing sorafenib's cytotoxicity where thyroid hormone T3 is utilized to modulate AKT expression to combat resistance, and warrant further studies in the field.
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Affiliation(s)
- Sude Uyulgan
- İzmir University of Economics, Faculty of Engineering, Department of Genetics and Bioengineering, 35330, Balçova, İzmir, Turkey
- İzmir Biomedicine and Genome Center (IBG), Dokuz Eylül University Health Campus, 35340, İnciraltı, İzmir, Turkey
- İzmir International Biomedicine and Genome Institute (iBG-İzmir), Dokuz Eylül University, 35340, İnciraltı, İzmir, Turkey
| | - Sıla Naz Köse
- İzmir University of Economics, Faculty of Engineering, Department of Genetics and Bioengineering, 35330, Balçova, İzmir, Turkey
| | - Arda Kıpçak
- İzmir University of Economics, Faculty of Engineering, Department of Genetics and Bioengineering, 35330, Balçova, İzmir, Turkey
- Present Adress: Department of Psychology, University of Virginia, Charlottesville, VA, 22903 USA
| | - Yağmur Başkan
- İzmir University of Economics, Faculty of Engineering, Department of Genetics and Bioengineering, 35330, Balçova, İzmir, Turkey
| | - Gökçe Dağlar
- İzmir University of Economics, Faculty of Engineering, Department of Genetics and Bioengineering, 35330, Balçova, İzmir, Turkey
| | - Zeynep Fırtına Karagonlar
- İzmir University of Economics, Faculty of Engineering, Department of Genetics and Bioengineering, 35330, Balçova, İzmir, Turkey
| | - Cihangir Yandım
- İzmir University of Economics, Faculty of Engineering, Department of Genetics and Bioengineering, 35330, Balçova, İzmir, Turkey
- İzmir Biomedicine and Genome Center (IBG), Dokuz Eylül University Health Campus, 35340, İnciraltı, İzmir, Turkey
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Zhou XC, Ni GX. O-linked β-N-acetylglucosaminylation may be a key regulatory factor in promoting osteogenic differentiation of bone marrow mesenchymal stromal cells. World J Stem Cells 2024; 16:228-231. [PMID: 38577231 PMCID: PMC10989286 DOI: 10.4252/wjsc.v16.i3.228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/02/2024] [Accepted: 02/29/2024] [Indexed: 03/25/2024] Open
Abstract
Cumulative evidence suggests that O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) plays an important regulatory role in pathophysiological processes. Although the regulatory mechanisms of O-GlcNAcylation in tumors have been gradually elucidated, the potential mechanisms of O-GlcNAcylation in bone metabolism, particularly, in the osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs) remains unexplored. In this study, the literature related to O-GlcNAcylation and BMSC osteogenic differentiation was reviewed, assuming that it could trigger more scholars to focus on research related to O-GlcNAcylation and bone metabolism and provide insights into the development of novel therapeutic targets for bone metabolism disorders such as osteoporosis.
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Affiliation(s)
- Xu-Chang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Guo-Xin Ni
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China.
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Ayoub SE, Shaker OG, Aboshama RA, Etman MK, Khalefa AA, khamiss Abd elguaad MM, Zaki OM, Ali DY, Hemeda NF, Amin A, Ali MA. Expression profile of LncRNA ANRIL, miR-186, miR-181a, and MTMR-3 in patients with preeclampsia. Noncoding RNA Res 2023; 8:481-486. [PMID: 37456780 PMCID: PMC10344750 DOI: 10.1016/j.ncrna.2023.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/18/2023] [Accepted: 06/06/2023] [Indexed: 07/18/2023] Open
Abstract
Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Several studies demonstrated the role of lncRNAs and miRNAs in the pathogenesis of preeclampsia; the aim was to detect the expression profiles of serum LncRNA ANRIL, miR-186, miR-181a, and MTMR-3 in patients with preeclampsia. The study included 160 subjects divided into 80 subjects considered as a control group, 80 patients with preeclampsia. We found that there was a significant difference between the preeclampsia and control groups with up-regulation of miR-186 median (IQR) = 4, 29 (1.35-7.73) (P < 0.0001), miR-181a median (IQR) = 2.45 (0.83-6.52) (P = 0.028), and downregulation of lncRNA ANRIL median (IQR) = 0.35(0.28-0.528) (P < 0.0001), MTMR median (IQR) = 0.32(0.155-1.11), (P < 0.0001). ROC curve of lncRNA ANRIL, miR-186, miR-181a, and MTMR-3 in preeclampsia patients showing the roles of these markers in the diagnosis of preeclampsia. In conclusion, serum LncRNA ANRIL, miR-186, miR-181a, and MTMR-3 could be promising biomarkers in the diagnosis of preeclampsia.
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Affiliation(s)
- Shymaa E. Ayoub
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Olfat G. Shaker
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Mohamed K. Etman
- Department of Obstetrics and Gynecology, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Abeer A. Khalefa
- Department of Physiology, Faculty of Medicine, Zagazig University, El Zagazig, Egypt
| | | | - Othman M. Zaki
- Department of Clinical Pathology, Faculty of Medicine, Damietta University, Damietta, Egypt
| | - Doaa Y. Ali
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Nada F. Hemeda
- Department of Genetics, Faculty of Agriculture, Fayoum University, Fayoum, Egypt
| | - Amal Amin
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Marwa A. Ali
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
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Wu H, Chen G, Zhang G, Lv Q, Gu D, Dai M. Mechanism of vascular endothelial cell-derived exosomes modified with vascular endothelial growth factor in steroid-induced femoral head necrosis. Biomed Mater 2023; 18. [PMID: 36794758 DOI: 10.1088/1748-605x/acb412] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 01/17/2023] [Indexed: 02/17/2023]
Abstract
Steroid-induced avascular necrosis of the femoral head (SANFH) is an intractable orthopedic disease. This study investigated the regulatory effect and molecular mechanism of vascular endothelial cell (VEC)-derived exosomes (Exos) modified with vascular endothelial growth factor (VEGF) in osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in SANFH. VECs were culturedin vitroand transfected with adenovirus Adv-VEGF plasmids. Exos were extracted and identified.In vitro/vivoSANFH models were established and treated with VEGF-modified VEC-Exos (VEGF-VEC-Exos). The internalization of Exos by BMSCs, proliferation and osteogenic and adipogenic differentiation of BMSCs were determined by the uptake test, cell counting kit-8 (CCK-8) assay, alizarin red staining, and oil red O staining. Meanwhile, the mRNA level of VEGF, the appearance of the femoral head, and histological analysis were assessed by reverse transcription quantitative polymerase chain reaction and hematoxylin-eosin staining. Moreover, the protein levels of VEGF, osteogenic markers, adipogenic markers, and mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinases (ERK) pathway-related indicators were examined by Western blotting, along with evaluation of the VEGF levels in femur tissues by immunohistochemistry. Glucocorticoid (GC) induced adipogenic differentiation of BMSCs and inhibited osteogenic differentiation. VEGF-VEC-Exos accelerated the osteogenic differentiation of GC-induced BMSCs and inhibited adipogenic differentiation. VEGF-VEC-Exos activated the MAPK/ERK pathway in GC-induced BMSCs. VEGF-VEC-Exos promoted osteoblast differentiation and suppressed adipogenic differentiation of BMSCs by activating the MAPK/ERK pathway. VEGF-VEC-Exos accelerated bone formation and restrained adipogenesis in SANFH rats. VEGF-VEC-Exos carried VEGF into BMSCs and motivated the MAPK/ERK pathway, thereby promoting osteoblast differentiation of BMSCs in SANFH, inhibiting adipogenic differentiation, and alleviating SANFH.
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Affiliation(s)
- Hongliang Wu
- Department of Orthopedics, Shanghai Punan Hospital of Pudong New District, Shanghai 200125, People's Republic of China
| | - Guocheng Chen
- Department of Orthopedics, Shanghai Punan Hospital of Pudong New District, Shanghai 200125, People's Republic of China
| | - Guibao Zhang
- Department of Orthopedics, Shanghai Punan Hospital of Pudong New District, Shanghai 200125, People's Republic of China
| | - Qiang Lv
- Department of Orthopedics, Shanghai Punan Hospital of Pudong New District, Shanghai 200125, People's Republic of China
| | - Di Gu
- Department of Orthopedics, Shanghai Punan Hospital of Pudong New District, Shanghai 200125, People's Republic of China
| | - Minhua Dai
- Department of Orthopedics, Shanghai Punan Hospital of Pudong New District, Shanghai 200125, People's Republic of China
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Fan S, Huang Y, Lu G, Sun N, Wang R, Lu C, Ding L, Han J, Zhou J, Li Y, Ming T, Su X. Novel anti-hyperuricemic hexapeptides derived from Apostichopus japonicus hydrolysate and their modulation effects on the gut microbiota and host microRNA profile. Food Funct 2022; 13:3865-3878. [PMID: 35274663 DOI: 10.1039/d1fo03981d] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hyperuricemia (HUA) is the second most common metabolic disease nowadays, and is characterized by permanently increased concentrations of serum uric acid. In this study, two novel hexapeptides (GPAGPR and GPSGRP) were identified from Apostichopus japonicus hydrolysate and predicted to have xanthine oxidase (XOD) inhibitory activity by molecular docking. Their in vitro XOD inhibition rates reached 37.3% and 48.6%, respectively, at a concentration of 40 mg mL-1. Subsequently, in vivo experiments were carried out in a HUA mouse model, and we found that both peptides reduced the serum uric acid by inhibiting uric acid biosynthesis and reabsorption, as well as alleviated renal inflammation via suppressing the activation of the NLRP3 inflammasome. 16S rDNA sequencing indicated that both peptide treatments reduced the richness and diversity of the gut microbiota, altered the composition in the phylum and genus levels, but different change trends were observed in the phylum Verrucomicrobia and genera Akkermansia, Dubosiella, Alloprevotella, Clostridium unclassified and Alistipes. In addition, changes in the renal microRNA (miRNA) profiles induced by GPSGRP treatment were analyzed; 21 differentially expressed (DE) miRNAs were identified among groups, and KEGG pathway analysis indicated that their potential target genes were involved in pluripotency of stem cell regulation, mTOR signaling pathway and proteoglycans. Moreover, ten miRNAs involved in the HUA onset and alleviation were identified, which showed a high correlation with genera related to the metabolism of short-chain fatty acids, bile acids and tryptophan. This study delineated two hexapeptides as potential microbiota modulators and miRNA regulators that can ameliorate HUA.
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Affiliation(s)
- Siqing Fan
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China
| | - Yumeng Huang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Guoding Lu
- Ningbo Green-Health Pharmaceutical Co., Ltd, Ningbo, China
| | - Na Sun
- Ningbo Green-Health Pharmaceutical Co., Ltd, Ningbo, China
| | - Rui Wang
- College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China
| | - Chenyang Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Lijian Ding
- College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China
| | - Jiaojiao Han
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Jun Zhou
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Ye Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Tinghong Ming
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Xiurong Su
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
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