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1
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Çaydere M, Şahin Ö. Does halofuginone influence regeneration after peripheral nerve injury? J Orthop Surg Res 2025; 20:331. [PMID: 40170030 PMCID: PMC11959954 DOI: 10.1186/s13018-025-05758-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 03/25/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Halofuginone is an antiprotozoal drug with antifibrotic and anti-inflammatory properties. The aim of our study was to determine the effects of halofuginone on nerve recovery in sciatic nerve injury and compare it with steroid treatment. METHODS The left sciatic nerves of Sham subjects were exposed without intervention. The nerves of trauma animals were transected and sutured. In the methylprednisolone group and in the trauma group, after nerve transection and repair, 1 mg/kg methylprednisolone per day was administered intraperitoneally for seven days; in the halofuginone group and in the trauma group, after nerve transection and repair, 0.2 mg/kg halofuginone per day was administered orally by gavage for seven days. The rats were functionally evaluated at 4 and 8 weeks through walking path analysis. Pathological-morphometric, immunostaining-quantitative, and muscle weight measurements were performed at 8 weeks. RESULTS Compared with the trauma group, the methylprednisolone and the halofuginone groups had better functional outcomes (p < 0.001). Statistically significant difference was found in comparisons of the pathological and immunostaining results of the methylprednisolone and halofuginone groups (Respectively, nerve diameter (p = 0.007) and edema (P = 0.009)). CONCLUSION Halofuginone positively contributed to recovery after sciatic nerve injury. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Muzaffer Çaydere
- Department of Pathology, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey.
| | - Ömer Şahin
- Department of Neurosurgery, Bestepe State Hospital, Ankara, 06560, Turkey
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2
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Han Y, Liu S, Zhu J, Liu P, Meng Z, Li Y, Li S, Fan F, Zhang M, Liu H. Experimental study on the inhibitory effect of Halofuginone on NSCLC. Eur J Pharmacol 2025; 988:177221. [PMID: 39710292 DOI: 10.1016/j.ejphar.2024.177221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 12/09/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
In recent decades, significant advancements have been achieved in non-small cell lung cancer (NSCLC) treatment. However, drug resistance, postoperative recurrence, distant metastasis, and other critical issues arise during NSCLC treatment. Natural products play a crucial role in the development of anti-tumor drugs. Halofuginone (HF) is a derivative of Febrifugine, an extract of Dichroa febrifuga Lour, a traditional Chinese medicine. Recent studies on HF have demonstrated its antitumor activity and great potential for clinical applications. However, its antitumor effects and mechanisms in NSCLC remain unknown. This study aimed to elucidate the antitumor effect of HF on NSCLC and preliminarily explore its mechanism of action. The proliferation-related assay revealed that HF could inhibit the proliferation of lung adenocarcinoma cells HCC827 and H1975. Network pharmacology of HF and NSCLC indicated that HF could induce cellular oxidative stress, and the antitumor effect was related to autophagy, apoptosis, and cell cycle arrest. Experimental analysis using flow cytometry and western blotting confirmed that HF indeed induced autophagy, enhanced apoptosis, and caused cell cycle arrest. The addition of N-acetyl-cysteamine acid inhibits the HF-induced increase in reactive oxygen species levels, inhibits autophagy and apoptosis, and alters cell cycle distribution. The HCC827 transplantation tumor animal model established that HF substantially inhibited the growth of transplanted tumors. These findings suggest that HF exerts a significant inhibitory effect on NSCLC in vivo and in vitro. The inhibitory effect of HF on NSCLC was associated with the increase of ROS in tumor cells, induction of autophagy and apoptosis, and cell cycle arrest.
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Affiliation(s)
- Yuehua Han
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Shiyao Liu
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Juan Zhu
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Peipei Liu
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Zixuan Meng
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Yongping Li
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Shanshan Li
- School of Pharmacy, Bengbu Medical University, Bengbu, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China
| | - Fangtian Fan
- School of Pharmacy, Bengbu Medical University, Bengbu, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China
| | - Mengxiao Zhang
- School of Pharmacy, Bengbu Medical University, Bengbu, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China.
| | - Hao Liu
- School of Pharmacy, Bengbu Medical University, Bengbu, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China.
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3
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Ozmen E, Demir TD, Ozcan G. Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer. Front Mol Biosci 2024; 11:1340124. [PMID: 38562556 PMCID: PMC10982390 DOI: 10.3389/fmolb.2024.1340124] [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: 11/17/2023] [Accepted: 01/31/2024] [Indexed: 04/04/2024] Open
Abstract
Enhanced knowledge of the interaction of cancer cells with their environment elucidated the critical role of tumor microenvironment in tumor progression and chemoresistance. Cancer-associated fibroblasts act as the protagonists of the tumor microenvironment, fostering the metastasis, stemness, and chemoresistance of cancer cells and attenuating the anti-cancer immune responses. Gastric cancer is one of the most aggressive cancers in the clinic, refractory to anti-cancer therapies. Growing evidence indicates that cancer-associated fibroblasts are the most prominent risk factors for a poor tumor immune microenvironment and dismal prognosis in gastric cancer. Therefore, targeting cancer-associated fibroblasts may be central to surpassing resistance to conventional chemotherapeutics, molecular-targeted agents, and immunotherapies, improving survival in gastric cancer. However, the heterogeneity in cancer-associated fibroblasts may complicate the development of cancer-associated fibroblast targeting approaches. Although single-cell sequencing studies started dissecting the heterogeneity of cancer-associated fibroblasts, the research community should still answer these questions: "What makes a cancer-associated fibroblast protumorigenic?"; "How do the intracellular signaling and the secretome of different cancer-associated fibroblast subpopulations differ from each other?"; and "Which cancer-associated fibroblast subtypes predominate specific cancer types?". Unveiling these questions can pave the way for discovering efficient cancer-associated fibroblast targeting strategies. Here, we review current knowledge and perspectives on these questions, focusing on how CAFs induce aggressiveness and therapy resistance in gastric cancer. We also review potential therapeutic approaches to prevent the development and activation of cancer-associated fibroblasts via inhibition of CAF inducers and CAF markers in cancer.
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Affiliation(s)
- Ece Ozmen
- Koç University Graduate School of Health Sciences, Istanbul, Türkiye
| | - Tevriz Dilan Demir
- Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Türkiye
| | - Gulnihal Ozcan
- Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Türkiye
- Department of Medical Pharmacology, Koç University School of Medicine, Istanbul, Türkiye
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4
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Motofei IG. Biology of cancer; from cellular and molecular mechanisms to developmental processes and adaptation. Semin Cancer Biol 2022; 86:600-615. [PMID: 34695580 DOI: 10.1016/j.semcancer.2021.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/21/2021] [Accepted: 10/10/2021] [Indexed: 02/07/2023]
Abstract
Cancer research has been largely focused on the cellular and molecular levels of investigation. Recent data show that not only the cell but also the extracellular matrix plays a major role in the progression of malignancy. In this way, the cells and the extracellular matrix create a specific local microenvironment that supports malignant development. At the same time, cancer implies a systemic evolution which is closely related to developmental processes and adaptation. Consequently, there is currently a real gap between the local investigation of cancer at the microenvironmental level, and the pathophysiological approach to cancer as a systemic disease. In fact, the cells and the matrix are not only complementary structures but also interdependent components that act synergistically. Such relationships lead to cell-matrix integration, a supracellular form of biological organization that supports tissue development. The emergence of this supracellular level of organization, as a structure, leads to the emergence of the supracellular control of proliferation, as a supracellular function. In humans, proliferation is generally involved in developmental processes and adaptation. These processes suppose a specific configuration at the systemic level, which generates high-order guidance for local supracellular control of proliferation. In conclusion, the supracellular control of proliferation act as an interface between the downstream level of cell division and differentiation, and upstream level of developmental processes and adaptation. Understanding these processes and their disorders is useful not only to complete the big picture of malignancy as a systemic disease, but also to open new treatment perspectives in the form of etiopathogenic (supracellular or informational) therapies.
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Affiliation(s)
- Ion G Motofei
- Department of Oncology/ Surgery, Carol Davila University, St. Pantelimon Hospital, Dionisie Lupu Street, No. 37, Bucharest, 020021, Romania.
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5
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Zhang J, Xu Z, Li Y, Hu Y, Tang J, Xu J, Luo Y, Wu F, Sun X, Tang Y, Wang S. Theranostic mesoporous platinum nanoplatform delivers halofuginone to remodel extracellular matrix of breast cancer without systematic toxicity. Bioeng Transl Med 2022. [DOI: 10.1002/btm2.10427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Jie Zhang
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Ziqing Xu
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Yang Li
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Yongzhi Hu
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Jiajia Tang
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Jiaqi Xu
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Yafei Luo
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Feiyun Wu
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Xiaolian Sun
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Department of Pharmaceutical Analysis China Pharmaceutical University Nanjing China
| | - Yuxia Tang
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
| | - Shouju Wang
- Laboratory of Molecular Imaging, Department of Radiology The First Affiliated Hospital of Nanjing Medical University Nanjing China
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6
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Ucaryilmaz Metin C, Ozcan G. Comprehensive bioinformatic analysis reveals a cancer-associated fibroblast gene signature as a poor prognostic factor and potential therapeutic target in gastric cancer. BMC Cancer 2022; 22:692. [PMID: 35739492 PMCID: PMC9229147 DOI: 10.1186/s12885-022-09736-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/03/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Gastric cancer is one of the deadliest cancers, currently available therapies have limited success. Cancer-associated fibroblasts (CAFs) are pivotal cells in the stroma of gastric tumors posing a great risk for progression and chemoresistance. The poor prognostic signature for CAFs is not clear in gastric cancer, and drugs that target CAFs are lacking in the clinic. In this study, we aim to identify a poor prognostic gene signature for CAFs, targeting which may increase the therapeutic success in gastric cancer. METHODS We analyzed four GEO datasets with a network-based approach and validated key CAF markers in The Cancer Genome Atlas (TCGA) and The Asian Cancer Research Group (ACRG) cohorts. We implemented stepwise multivariate Cox regression guided by a pan-cancer analysis in TCGA to identify a poor prognostic gene signature for CAF infiltration in gastric cancer. Lastly, we conducted a database search for drugs targeting the signature genes. RESULTS Our study revealed the COL1A1, COL1A2, COL3A1, COL5A1, FN1, and SPARC as the key CAF markers in gastric cancer. Analysis of the TCGA and ACRG cohorts validated their upregulation and poor prognostic significance. The stepwise multivariate Cox regression elucidated COL1A1 and COL5A1, together with ITGA4, Emilin1, and TSPAN9 as poor prognostic signature genes for CAF infiltration. The search on drug databases revealed collagenase clostridium histolyticum, ocriplasmin, halofuginone, natalizumab, firategrast, and BIO-1211 as the potential drugs for further investigation. CONCLUSIONS Our study demonstrated the central role of extracellular matrix components secreted and remodeled by CAFs in gastric cancer. The gene signature we identified in this study carries high potential as a predictive tool for poor prognosis in gastric cancer patients. Elucidating the mechanisms by which the signature genes contribute to poor patient outcomes can lead to the discovery of more potent molecular-targeted agents and increase the therapeutic success in gastric cancer.
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Affiliation(s)
| | - Gulnihal Ozcan
- Department of Medical Pharmacology, Koc University School of Medicine, 34450, Istanbul, Turkey.
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Khan K, Gogonea V, Fox PL. Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis. Transl Oncol 2022; 19:101392. [PMID: 35278792 PMCID: PMC8914993 DOI: 10.1016/j.tranon.2022.101392] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 12/16/2022] Open
Abstract
In mammalian cells, 20 aminoacyl-tRNA synthetases (AARS) catalyze the ligation of amino acids to their cognate tRNAs to generate aminoacylated-tRNAs. In higher eukaryotes, 9 of the 20 AARSs, along with 3 auxiliary proteins, join to form the cytoplasmic multi-tRNA synthetase complex (MSC). The complex is absent in prokaryotes, but evolutionary expansion of MSC constituents, primarily by addition of novel interacting domains, facilitates formation of subcomplexes that join to establish the holo-MSC. In some cases, environmental cues direct the release of constituents from the MSC which enables the execution of non-canonical, i.e., "moonlighting", functions distinct from their essential activities in protein translation. These activities are generally beneficial, but can also be deleterious to the cell. Elucidation of the non-canonical activities of several AARSs residing in the MSC suggest they are potential therapeutic targets for cancer, as well as metabolic and neurologic diseases. Here, we describe the role of MSC-resident AARSs in cancer progression, and the factors that regulate their release from the MSC. Also, we highlight recent developments in therapeutic modalities that target MSC AARSs for cancer prevention and treatment.
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Affiliation(s)
- Krishnendu Khan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America.
| | - Valentin Gogonea
- Department of Chemistry, Cleveland State University, Cleveland, OH 44115, United States of America
| | - Paul L Fox
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America.
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8
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Lv T, Huang J, Wu M, Wang H, Zeng Q, Wang X. Halofuginone enhances the anti-tumor effect of ALA-PDT by suppressing NRF2 signaling in cSCC. Photodiagnosis Photodyn Ther 2022; 37:102572. [PMID: 34628069 DOI: 10.1016/j.pdpdt.2021.102572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND 5-aminolevulinic acid-mediated PDT (ALA-PDT) has been used in a variety of skin diseases including cSCC (cutaneous squamous cell carcinoma). Halofuginone (HL) is a less-toxic febrifugine derivative and has inhibitory effects on a variety of cancer cells. For now, there are no published study focusing on the combination use of ALA-PDT with HL to improve clinical efficacy of cSCC. OBJECTIVE In this study, we will examine the effectiveness of combined treatment of ALA-PDT and HL in cSCC as well as its underlying mechanism. METHODS The human epidermoid carcinoma cell line SCL-1 was treated with ALA-PDT or/ and HL, and cell viability, cell migration, ROS production, apoptosis were evaluated by CCK-8, colony formation, scratch assay, DCFH-DA probe, flow cytometry, respectively. The protein expression of NRF2 signaling was examined by western blot. RESULTS HL strengthened ALA-PDT's inhibition of SCL-1 cell viability, migration, as well as NRF2 related β-catenin, p-Erk1/2, p-Akt and p-S6K1 expression. Overexpression of NRF2 conferred resistance to co-treatment's effects on c-Myc, Cyclin D1, Bcl-2, as well as cell proliferation. HL also strengthened ALA-PDT's inhibition of tumor volume in cSCC mouse model and elevated ROS generation of ALA-PDT. CONCLUSION HL enhances the anti-tumor effect of ALA-PDT in vitro and in vivo. HL has the potential to enhance the anti-tumor effect of ALA-PDT in cSCC via inhibiting NRF2 signaling.
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Affiliation(s)
- Ting Lv
- Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jianhua Huang
- Department of Dermatology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - Minfeng Wu
- Department of Dermatology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - Hongwei Wang
- Department of Dermatology, Huadong Hospital, Fudan University, Shanghai 200040, China.
| | - Qingyu Zeng
- Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
| | - Xiuli Wang
- Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
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Takada S, Setoyama K, Norimatsu K, Otsuka S, Nakanishi K, Tani A, Nakakogawa T, Matsuzaki R, Matsuoka T, Sakakima H, Tancharoen S, Maruyama I, Tanaka E, Kikuchi K, Uchikado H. E8002 Reduces Adhesion Formation and Improves Joint Mobility in a Rat Model of Knee Arthrofibrosis. Int J Mol Sci 2022; 23:ijms23031239. [PMID: 35163163 PMCID: PMC8835358 DOI: 10.3390/ijms23031239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/19/2022] [Accepted: 01/21/2022] [Indexed: 11/26/2022] Open
Abstract
Knee arthrofibrosis is a common complication of knee surgery, caused by excessive scar tissue, which results in functional disability. However, no curative treatment has been established. E8002 is an anti-adhesion material that contains L-ascorbic acid, an antioxidant. We aimed to evaluate the efficacy of E8002 for the prevention of knee arthrofibrosis in a rat model, comprising injury to the surface of the femur and quadriceps muscle 1 cm proximal to the patella. Sixteen male, 8-week-old Sprague Dawley rats were studied: in the Adhesion group, haemorrhagic injury was induced to the quadriceps and bone, and in the E8002 group, an adhesion-preventing film was implanted between the quadriceps and femur after injury. Six weeks following injury, the restriction of knee flexion owing to fibrotic scarring had not worsened in the E8002 group but had worsened in the Adhesion group. The area of fibrotic scarring was smaller in the E8002 group than in the Adhesion group (p < 0.05). In addition, the numbers of fibroblasts (p < 0.05) and myofibroblasts (p < 0.01) in the fibrotic scar were lower in the E8002 group. Thus, E8002 reduces myofibroblast proliferation and fibrotic scar formation and improves the range of motion of the joint in a model of knee injury.
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Affiliation(s)
- Seiya Takada
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan; (S.T.); (S.O.); (I.M.)
| | - Kentaro Setoyama
- Division of Laboratory Animal Science, Natural Science Center for Research and Education, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan;
| | - Kosuke Norimatsu
- Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; (K.N.); (K.N.); (A.T.); (T.N.); (R.M.); (T.M.); (H.S.)
| | - Shotaro Otsuka
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan; (S.T.); (S.O.); (I.M.)
| | - Kazuki Nakanishi
- Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; (K.N.); (K.N.); (A.T.); (T.N.); (R.M.); (T.M.); (H.S.)
| | - Akira Tani
- Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; (K.N.); (K.N.); (A.T.); (T.N.); (R.M.); (T.M.); (H.S.)
| | - Tomomi Nakakogawa
- Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; (K.N.); (K.N.); (A.T.); (T.N.); (R.M.); (T.M.); (H.S.)
| | - Ryoma Matsuzaki
- Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; (K.N.); (K.N.); (A.T.); (T.N.); (R.M.); (T.M.); (H.S.)
| | - Teruki Matsuoka
- Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; (K.N.); (K.N.); (A.T.); (T.N.); (R.M.); (T.M.); (H.S.)
| | - Harutoshi Sakakima
- Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; (K.N.); (K.N.); (A.T.); (T.N.); (R.M.); (T.M.); (H.S.)
| | - Salunya Tancharoen
- Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok 10400, Thailand;
| | - Ikuro Maruyama
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan; (S.T.); (S.O.); (I.M.)
| | - Eiichiro Tanaka
- Division of Brain Science, Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan;
| | - Kiyoshi Kikuchi
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan; (S.T.); (S.O.); (I.M.)
- Division of Brain Science, Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan;
- Department of Neurosurgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
- Correspondence: (K.K.); (H.U.); Tel.: +81-942-31-7542 (K.K.); +81-92-477-2355 (H.U.); Fax: +81-942-31-7695 (K.K.); +81-92-477-2325 (H.U.)
| | - Hisaaki Uchikado
- Department of Neurosurgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
- Uchikado Neuro-Spine Clinic, 1-2-3 Naka, Hakata-ku, Fukuoka 812-0893, Japan
- Correspondence: (K.K.); (H.U.); Tel.: +81-942-31-7542 (K.K.); +81-92-477-2355 (H.U.); Fax: +81-942-31-7695 (K.K.); +81-92-477-2325 (H.U.)
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10
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Gong RH, Yang DJ, Kwan HY, Lyu AP, Chen GQ, Bian ZX. Cell death mechanisms induced by synergistic effects of halofuginone and artemisinin in colorectal cancer cells. Int J Med Sci 2022; 19:175-185. [PMID: 34975311 PMCID: PMC8692125 DOI: 10.7150/ijms.66737] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/16/2021] [Indexed: 12/11/2022] Open
Abstract
Our previous study found that the combination of halofuginone (HF) and artemisinin (ATS) synergistically arrest colorectal cancer (CRC) cells at the G1/G0 phase of the cell cycle; however, it remains unclear whether HF-ATS induces cell death. Here we report that HF-ATS synergistically induced caspase-dependent apoptosis in CRC cells. Specifically, both in vitro and in vivo experiments showed that HF or HF-ATS induces apoptosis via activation of caspase-9 and caspase-8 while only caspase-9 is involved in ATS-induced apoptosis. Furthermore, we found HF or HF-ATS induces autophagy; ATS can't induce autophagy until caspase-9 is blocked. Further analyzing the crosstalk between autophagic and caspase activation in CRC cells, we found autophagy is essential for activation of caspase-8, and ATS switches to activate capase-8 via induction of autophagy when caspase-9 is inhibited. When apoptosis is totally blocked, HF-ATS switches to induce autophagic cell death. This scenario was then confirmed in studies of chemoresistance CRC cells with defective apoptosis. Our results indicate that HF-ATS induces cell death via interaction between apoptosis and autophagy in CRC cells. These results highlight the value of continued investigation into the potential use of this combination in cancer therapy.
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Affiliation(s)
- Rui-Hong Gong
- Centre for Cancer and Inflammation Research (CCIR), School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong S.A.R., China
| | - Da-Jian Yang
- Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China
| | - Hiu-Yee Kwan
- Centre for Cancer and Inflammation Research (CCIR), School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong S.A.R., China
| | - Ai-Ping Lyu
- Centre for Cancer and Inflammation Research (CCIR), School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong S.A.R., China
| | - Guo-Qing Chen
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen 518057, China
- Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China
| | - Zhao-Xiang Bian
- Centre for Cancer and Inflammation Research (CCIR), School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong S.A.R., China
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Wang J, Wang B, Lv X, Wang Y. Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model. Int J Immunopathol Pharmacol 2021; 34:2058738420974893. [PMID: 33259259 PMCID: PMC7716055 DOI: 10.1177/2058738420974893] [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] [Indexed: 02/06/2023] Open
Abstract
Periodontitis is an inflammatory disease caused by host immune response, resulting in a loss of periodontium and alveolar bone. Immune cells, such as T cells and macrophages, play a critical role in the periodontitis onset. Halofuginone, a natural quinazolinone alkaloid, has been shown to possess anti-fibrosis, anti-cancer, and immunomodulatory properties. However, the effect of halofuginone on periodontitis has never been reported. In this study, a ligature-induced mice model of periodontitis was applied to investigate the potential beneficial effect of halofuginone on periodontitis. We demonstrated that the administration of halofuginone significantly reduced the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in vivo, and markedly suppressed immune cell infiltration into the infected sites. Furthermore, we also observed that halofuginone treatment blocked the T-helper 17 (Th17) cell differentiation in vivo and in vitro. We demonstrated for the first time that halofuginone alleviated the onset of periodontitis through reducing immune responses.
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Affiliation(s)
- Jiang Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of General Dentistry & Emergency, the Hospital of Stomatology, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Bo Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Digital Center, the Hospital of Stomatology, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xin Lv
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of General Dentistry & Emergency, the Hospital of Stomatology, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yingjie Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of General Dentistry & Emergency, the Hospital of Stomatology, the Fourth Military Medical University, Xi’an, Shaanxi, China
- Yingjie Wang, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of General Dentistry & Emergency, the Hospital of Stomatology, the Fourth Military Medical University, Xi’an, Shaanxi 710032, China.
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12
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Jain PP, Zhao T, Xiong M, Song S, Lai N, Zheng Q, Chen J, Carr SG, Babicheva A, Izadi A, Rodriguez M, Rahimi S, Balistrieri F, Rahimi S, Simonson T, Valdez-Jasso D, Thistlethwaite PA, Shyy JYJ, Wang J, Makino A, Yuan JXJ. Halofuginone, a promising drug for treatment of pulmonary hypertension. Br J Pharmacol 2021; 178:3373-3394. [PMID: 33694155 PMCID: PMC9792225 DOI: 10.1111/bph.15442] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 02/18/2021] [Accepted: 02/23/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Halofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti-hypertrophic, anti-fibrotic and anti-proliferative effects. We sought to investigate whether halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia-induced pulmonary hypertension (HPH). EXPERIMENTAL APPROACH Patch-clamp experiments were conducted to examine the activity of voltage-dependent Ca2+ channels (VDCCs) in pulmonary artery smooth muscle cells (PASMCs). Digital fluorescence microscopy was used to measure intracellular Ca2+ concentration in PASMCs. Isolated perfused and ventilated mouse lungs were used to measure pulmonary artery pressure (PAP). Mice exposed to hypoxia (10% O2 ) for 4 weeks were used as model of HPH for in vivo experiments. KEY RESULTS Halofuginone increased voltage-gated K+ (Kv ) currents in PASMCs and K+ currents through KCNA5 channels in HEK cells transfected with KCNA5 gene. HF (0.03-1 μM) inhibited receptor-operated Ca2+ entry in HEK cells transfected with calcium-sensing receptor gene and attenuated store-operated Ca2+ entry in PASMCs. Acute (3-5 min) intrapulmonary application of halofuginone significantly and reversibly inhibited alveolar hypoxia-induced pulmonary vasoconstriction dose-dependently (0.1-10 μM). Intraperitoneal administration of halofuginone (0.3 mg·kg-1 , for 2 weeks) partly reversed established PH in mice. CONCLUSION AND IMPLICATIONS Halofuginone is a potent pulmonary vasodilator by activating Kv channels and blocking VDCC and receptor-operated and store-operated Ca2+ channels in PASMCs. The therapeutic effect of halofuginone on experimental PH is probably due to combination of its vasodilator effects, via inhibition of excitation-contraction coupling and anti-proliferative effects, via inhibition of the PI3K/Akt/mTOR signalling pathway.
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Affiliation(s)
- Pritesh P. Jain
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Tengteng Zhao
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Mingmei Xiong
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
- Department of Critical Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | | | - Ning Lai
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
- State Key Laboratory of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qiuyu Zheng
- Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA
| | - Jiyuan Chen
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
- State Key Laboratory of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | | | - Aleksandra Babicheva
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Amin Izadi
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Marisela Rodriguez
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Shamin Rahimi
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Francesca Balistrieri
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Shayan Rahimi
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Tatum Simonson
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Daniela Valdez-Jasso
- Department of Bioengineering, University of California, San Diego, La Jolla, California, USA
| | - Patricia A. Thistlethwaite
- Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - John Y.-J. Shyy
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Jian Wang
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
- State Key Laboratory of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ayako Makino
- Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA
| | - Jason X.-J. Yuan
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
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Yang H, Li Q, Su M, Luo F, Liu Y, Wang D, Fan Y. Design, synthesis, and biological evaluation of novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives as potential anticancer agents via PI3K inhibition. Bioorg Med Chem 2021; 46:116346. [PMID: 34403956 DOI: 10.1016/j.bmc.2021.116346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/18/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023]
Abstract
Abnormal activation of the PI3K/Akt pathway is demonstrated in most of human malignant tumors via regulation of proliferation, cell cycle, and apoptosis. Therefore, drug discovery and development of targeting the PI3K/Akt pathway has attracted great interest of researchers in the development of anticancer drugs. In this study, fifteen 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives were designed and synthesized. Anticancer activities of the synthetic compounds were evaluated and the potential mechanisms were explored. Several compounds showed certain proliferation inhibitory activity against the tested cancer cells including human non-small cell lung cancer (NSCLC) HCC827, human neuroblastoma SH-SY5Y and hepatocellular carcinoma LM3 cells. Among them, compound 7i and 7m showed the best inhibitory activity against all the cancer cell lines and more active against HCC827 cells with IC50 values of 1.12 μM and 1.20 μM, respectively. In addition, 7i and 7m showed lower inhibitory activity against H7702 cells (human normal liver cells) with IC50 values of 8.66 μM and 10.89 μM, respectively, nearly 8-fold lower than that in HCC827 cells. These results suggested that compounds 7i and 7m had certain selectivity to tumor cells, compared to human normal cells. Further biological studies indicated 7i induced G2/M phase arrests and cell apoptosis of HCC827 cells via PI3K/Akt and caspase dependent pathway. Together, these novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives such as compound 7i and 7m might be lead compounds for development of potential anti-cancer drugs.
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Affiliation(s)
- Huarong Yang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550002, PR China
| | - Qing Li
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China
| | - Mingzhi Su
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China
| | - Fang Luo
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China
| | - Yahua Liu
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550002, PR China.
| | - Daoping Wang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China.
| | - Yanhua Fan
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China.
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14
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Moriya K, Nishimura N, Namisaki T, Takaya H, Sawada Y, Kawaratani H, Kaji K, Shimozato N, Sato S, Furukawa M, Douhara A, Akahane T, Mitoro A, Yamao J, Yoshiji H. Zinc Administration and Improved Serum Markers of Hepatic Fibrosis in Patients with Autoimmune Hepatitis. J Clin Med 2021; 10:2465. [PMID: 34199421 PMCID: PMC8199625 DOI: 10.3390/jcm10112465] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/26/2021] [Accepted: 05/31/2021] [Indexed: 02/06/2023] Open
Abstract
AIM The aim of the present study is to investigate the effect of long-term zinc supplementation, which is important for the activation of various enzymes that contribute to antioxidant and antifibrotic activities, on the improvement of serum fibrotic markers in patients with autoimmune hepatitis (AIH). METHODS A total of 38 patients with AIH under regular treatment at our hospital who provided their consent for being treated with polaprezinc (75 mg twice daily) were included and classified into 2 groups: the patients with zinc elevation (n = 27) and the patients without zinc elevation (n = 11). Serum biomarker of fibrosis, protein expression levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were evaluated. RESULTS A significant difference was found between the variability of serum procollagen type Ⅲ and collagen type Ⅳ-7S between the 2 groups before and after zinc administration for more than 24 months (p = 0.043 and p = 0.049). In the patients with zinc elevation, no significant changes were found in collagenase (MMP-1 and MMP-13) before and after zinc administration, whereas a significant increase in the expression of gelatinase (MMP-2 and MMP-9) was found after administration (p = 0.021 and p = 0.005). As for the relative ratio of MMPs to TIMPs, only MMP-9 to TIMP-1 showed a significant increase (p = 0.004). CONCLUSIONS Long-term treatment with polaprezinc has been demonstrated to safely improve serum fibrosis indices through increases in MMP-2/-9 and MMP-9/TIMP-1 and is expected to be well combined with direct antifibrotic therapies such as molecularly targeted agents.
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Affiliation(s)
- Kei Moriya
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Norihisa Nishimura
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Tadashi Namisaki
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Hiroaki Takaya
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Yasuhiko Sawada
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Hideto Kawaratani
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Kosuke Kaji
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Naotaka Shimozato
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Shinya Sato
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Masanori Furukawa
- Department of Endoscopy, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (M.F.); (J.Y.)
| | - Akitoshi Douhara
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Takemi Akahane
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Akira Mitoro
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
| | - Junichi Yamao
- Department of Endoscopy, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (M.F.); (J.Y.)
| | - Hitoshi Yoshiji
- Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (N.N.); (T.N.); (H.T.); (Y.S.); (H.K.); (K.K.); (N.S.); (S.S.); (A.D.); (T.A.); (A.M.); (H.Y.)
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15
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Marty P, Chatelain B, Lihoreau T, Tissot M, Dirand Z, Humbert P, Senez C, Secomandi E, Isidoro C, Rolin G. Halofuginone regulates keloid fibroblast fibrotic response to TGF-β induction. Biomed Pharmacother 2021; 135:111182. [PMID: 33433355 DOI: 10.1016/j.biopha.2020.111182] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/14/2020] [Accepted: 12/26/2020] [Indexed: 01/06/2023] Open
Abstract
Keloids are characterized by increased deposition of fibrous tissue in the skin and subcutaneous tissue following an abnormal wound healing process. Although keloid etiology is yet to be fully understood, fibroblasts are known to be key players in its development. Here we analyze the antifibrotic mechanisms of Halofuginone (HF), a drug reportedly able to inhibit the TGF-β1-Smad3 pathway and to attenuate collagen synthesis, in an in-vitro keloid model using patient-derived Keloid Fibroblasts (KFs) isolated from fibrotic tissue collected during the "Scar Wars" clinical study (NCT NCT03312166). TGF-β1 was used as a pro-fibrotic agent to stimulate fibroblasts response under HF treatment. The fibrotic related properties of KFs, including survival, migration, proliferation, myofibroblasts conversion, ECM synthesis and remodeling, were investigated in 2D and 3D cultures. HF at 50 nM concentration impaired KFs proliferation, and decreased TGF-β1-induced expression of α-SMA and type I procollagen production. HF treatment also reduced KFs migration, prevented matrix contraction and increased the metallo-proteases/inhibitors (MMP/TIMP) ratio. Overall, HF elicits an anti-fibrotic contrasting the TGF-β1 stimulation of KFs, thus supporting its therapeutic use for keloid prevention and management.
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Affiliation(s)
- Pierre Marty
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France; Service de Chirurgie Maxillo-faciale, Stomatologie et Odontologie Hospitalière, CHU Besançon, F-25000, Besançon, France
| | - Brice Chatelain
- Service de Chirurgie Maxillo-faciale, Stomatologie et Odontologie Hospitalière, CHU Besançon, F-25000, Besançon, France
| | | | - Marion Tissot
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France
| | - Zélie Dirand
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France
| | - Philippe Humbert
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France
| | - Clémence Senez
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France
| | - Eleonora Secomandi
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy
| | - Ciro Isidoro
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.
| | - Gwenaël Rolin
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France; INSERM CIC-1431, CHU Besançon, F-25000, Besançon, France.
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16
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Abstract
Radiation-induced lung injury (RILI) is a common complication in cancer patients receiving local thoracic radiation and bone marrow transplantation conditioning. It is divided into early-stage radiation pneumonitis and advanced radiation fibrosis of the lung. This severely hampers the quality of life and survival of cancer patients. Meanwhile, RILI is a major factor limiting radiation doses in clinical practice, which affects the local control of cancer. Unfortunately, the mechanism of RILI is still not well defined, and there are no treatment options available for these patients. In this review we summarize the methods and agents used for the treatment and prevention of RILI, with the aim of increasing understanding of RILI.
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17
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Significance of halofuginone in esophageal squamous carcinoma cell apoptosis through HIF-1α-FOXO3a pathway. Life Sci 2020; 257:118104. [PMID: 32679143 DOI: 10.1016/j.lfs.2020.118104] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/07/2020] [Accepted: 07/12/2020] [Indexed: 12/19/2022]
Abstract
Halofuginone (HF) from Dichroa febrifuga has shown therapeutic potential in hepatocellular, lung and colorectal cancer cell models. Evidence has also indicated that HF plays roles in caustic induced esophageal strictures and oxidative injury. However, the role of HF in esophageal squamous carcinoma (ESCC) remains unclear. In this study, we investigated HF actions and mechanisms during ESCC cell apoptosis. We observed different HF concentrations (5, 10 and 20 nM) inhibited ESCC cell survival in a time and dose-dependent manner. HF treatment markedly induced KYSE-30 and TE-1 cell apoptosis, and caspase-3 activity. Apoptosis related protein Bax expression was dramatically increased, whereas Bcl-2 levels were reduced in KYSE-30 and TE-1 cells, after HF exposure. Also, we showed that HF treatment induced DNA damage by promoting γH2AX, pATM and pATR expression. HF treatment also reduced hypoxia-inducible factor-1α (HIF-1α) and forkhead box class O 3a (FOXO3a) expression in KYSE-30 and TE-1 cells. We also showed that HF inhibited FOXO3a expression, but this was dependent on HIF-1α inhibition. Finally, FOXO3a overexpression reversed HF induced cell survival inhibition, cell apoptosis and DNA damage. FOXO3a knockdown enhanced the effects of HF on cell survival, cell apoptosis and DNA damage. In summary, HF plays inhibitory roles in ESCC cell apoptosis, via HIF-1α-FOXO3a-dependent signaling. These data support the notion that HF could act as an effective therapeutic reagent towards ESCC.
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18
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Demiroglu-Zergeroglu A, Turhal G, Topal H, Ceylan H, Donbaloglu F, Karadeniz Cerit K, Odongo RR. Anticarcinogenic effects of halofuginone on lung-derived cancer cells. Cell Biol Int 2020; 44:1934-1944. [PMID: 32437065 DOI: 10.1002/cbin.11399] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/04/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
Malignant mesothelioma is a rare but aggressive form of malignancy, which is difficult to diagnose and is resistant to current chemotherapeutic treatment options. Molecular techniques have been used to investigate the mechanisms of action and the beneficial therapeutic effects of halofuginone (HF) in several cancers but not malignant mesotheliomas. In this study, the antiproliferative and apoptotic effects of HF were investigated through its ability to deregulate EGFR downstream signalling cascade proteins in the pathologically aggressive malignant mesothelioma and non-small-cell lung cancer cells. We showed that administration of HF at nanomolar concentrations induced a dose-dependent reduction in the viability of cancer cells, made cell cycle arrest, inhibited proliferation of cancer cells via STAT3 and ERK1/2 pathways and triggered the apoptotic cascade via p38MAPK. We demonstrated that the apoptotic cell death mechanism was mediated by enhanced activation of caspase-3 and concomitant PARP cleavage, downregulation of Bcl-2 and upregulation of Bax in both malignant mesothelioma and lung cancer cells. In particular, we demonstrated that cancer cells were more sensitive to HF treatment than normal mesothelial cells. Taken together, this study suggests that HF exerts its anticancer effects in lung-derived cancers by targeting signal transduction pathways mainly through deregulation of ERK1/2, STAT3 and p38MAPK to reduce cancer cell viability, induce cell cycle arrest and apoptotic cell death. Thus, HF might be considered as a potential agent against malignant mesothelioma and/or lung cancer cells.
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Affiliation(s)
- Asuman Demiroglu-Zergeroglu
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Gulseren Turhal
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Halime Topal
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Hurmuz Ceylan
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Fadime Donbaloglu
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Kivilcim Karadeniz Cerit
- Department of Pediatric Surgery, School of Medicine, Marmara University, Pendik, Istanbul, Turkey
| | - Ronald R Odongo
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
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19
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Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells. Proc Natl Acad Sci U S A 2020; 117:8900-8911. [PMID: 32253314 DOI: 10.1073/pnas.1913788117] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Signaling pathways that sense amino acid abundance are integral to tissue homeostasis and cellular defense. Our laboratory has previously shown that halofuginone (HF) inhibits the prolyl-tRNA synthetase catalytic activity of glutamyl-prolyl-tRNA synthetase (EPRS), thereby activating the amino acid response (AAR). We now show that HF treatment selectively inhibits inflammatory responses in diverse cell types and that these therapeutic benefits occur in cells that lack GCN2, the signature effector of the AAR. Depletion of arginine, histidine, or lysine from cultured fibroblast-like synoviocytes recapitulates key aspects of HF treatment, without utilizing GCN2 or mammalian target of rapamycin complex 1 pathway signaling. Like HF, the threonyl-tRNA synthetase inhibitor borrelidin suppresses the induction of tissue remodeling and inflammatory mediators in cytokine-stimulated fibroblast-like synoviocytes without GCN2, but both aminoacyl-tRNA synthetase (aaRS) inhibitors are sensitive to the removal of GCN1. GCN1, an upstream component of the AAR pathway, binds to ribosomes and is required for GCN2 activation. These observations indicate that aaRS inhibitors, like HF, can modulate inflammatory response without the AAR/GCN2 signaling cassette, and that GCN1 has a role that is distinct from its activation of GCN2. We propose that GCN1 participates in a previously unrecognized amino acid sensor pathway that branches from the canonical AAR.
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20
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Afroz S, Shama, Battu S, Matin S, Solouki S, Elmore JP, Minhas G, Huang W, August A, Khan N. Amino acid starvation enhances vaccine efficacy by augmenting neutralizing antibody production. Sci Signal 2019; 12:12/607/eaav4717. [PMID: 31719173 DOI: 10.1126/scisignal.aav4717] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Specific reduction in the intake of proteins or amino acids (AAs) offers enormous health benefits, including increased life span, protection against age-associated disorders, and improved metabolic fitness and immunity. Cells respond to conditions of AA starvation by activating the amino acid starvation response (AAR). Here, we showed that mimicking AAR with halofuginone (HF) enhanced the magnitude and affinity of neutralizing, antigen-specific antibody responses in mice immunized with dengue virus envelope domain III protein (DENVrEDIII), a potent vaccine candidate against DENV. HF enhanced the formation of germinal centers (GCs) and increased the production of the cytokine IL-10 in the secondary lymphoid organs of vaccinated mice. Furthermore, HF promoted the transcription of genes associated with memory B cell formation and maintenance and maturation of GCs in the draining lymph nodes of vaccinated mice. The increased abundance of IL-10 in HF-preconditioned mice correlated with enhanced GC responses and may promote the establishment of long-lived plasma cells that secrete antigen-specific, high-affinity antibodies. Thus, these data suggest that mimetics of AA starvation could provide an alternative strategy to augment the efficacy of vaccines against dengue and other infectious diseases.
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Affiliation(s)
- Sumbul Afroz
- School of Life Sciences, Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, 500046 Telangana, India
| | - Shama
- School of Life Sciences, Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, 500046 Telangana, India
| | - Srikanth Battu
- School of Life Sciences, Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, 500046 Telangana, India
| | - Shaikh Matin
- School of Life Sciences, Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, 500046 Telangana, India
| | - Sabrina Solouki
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Jessica P Elmore
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Gillipsie Minhas
- School of Life Sciences, Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, 500046 Telangana, India
| | - Weishan Huang
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.,Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | - Avery August
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Nooruddin Khan
- School of Life Sciences, Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, 500046 Telangana, India.
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21
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Ceylan SM, Uysal E, Sokucu M, Sezgin E, Kanmaz MA, Yurtseven DG, Bilal N. The Effects of Halofuginone on Wound Healing in the Rat Nasal Mucosa. Am J Rhinol Allergy 2019; 34:9-15. [PMID: 31438721 DOI: 10.1177/1945892419866312] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Background Halofuginone is an alkaloid febrifugine analogue and bioactive molecule that was isolated incidentally from the Dichroa febrifuga plant. The therapeutic efficacy of halofuginone in parasitic infections, scleroderma, inflammation, and fibrosis-related diseases, as well as in some types of cancer, has been previously reported. The effects of halofuginone on nasal mucosal damage are not yet known. Objective The aim of this study was to investigate the potential effect of topically applied halofuginone on wound healing in the mechanically injured nasal mucosa of rats. Methods A unilateral mucosal wound was created in the nasal cavity of 32 rats (aged 4 weeks) using the brushing technique. These rats were randomly divided into 4 groups. Although the control group did not receive an intervention, a dry pad, a saline-impregnated pad, or a pad impregnated with halofuginone were placed in the rats of the other 3 groups and left for 5 minutes. Rats were sacrificed on the 14th day, and a histological examination was performed. The nasal mucosa was assessed via hematoxylin-eosin and Masson’s trichrome staining. Results There were no statistically significant differences in epithelial thickness, inflammation, goblet cell formation, and epithelial disarray values between the halofuginone group and the control group ( P > .05). The subepithelial thickness was significantly decreased in the saline-treated group and the halofuginone-treated group ( P < .05), but a significantly lower level of subepithelial fibrosis was only observed in the halofuginone group compared to the other groups ( P < .05). Conclusions Topical halofuginone administration reduces the development of fibrosis and subepithelial edema after experimentally induced nasal mucosal injury, but it does not exert therapeutic or preventive effects on epithelial damage, inflammation, and goblet cell hyperplasia.
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Affiliation(s)
- Seyit Mehmet Ceylan
- Department of Otorhinolaryngology, Faculty of Medicine, SANKO University, Gaziantep, Turkey
| | - Erdal Uysal
- Department of General Surgery, Faculty of Medicine, SANKO University, Gaziantep, Turkey
| | - Mehmet Sokucu
- Department of Pathology, Faculty of Medicine, SANKO University, Gaziantep, Turkey
| | - Efe Sezgin
- Laboratory of Nutrigenomics and Epidemiology, Department of Food Engineering, Izmir Institute of Thechnology, Izmir, Turkey
| | - Mahmut Alper Kanmaz
- Department of Otorhinolaryngology, Faculty of Medicine, SANKO University, Gaziantep, Turkey
| | - Duygu Gok Yurtseven
- Department of Histology and Embryology, Faculty of Medicine, SANKO University, Gaziantep, Turkey
| | - Nagihan Bilal
- Department of Otorhinolaryngology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey
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22
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Usher KM, Zhu S, Mavropalias G, Carrino JA, Zhao J, Xu J. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Res 2019; 7:9. [PMID: 30937213 PMCID: PMC6433953 DOI: 10.1038/s41413-019-0047-x] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 02/17/2019] [Accepted: 02/26/2019] [Indexed: 02/07/2023] Open
Abstract
Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury, surgery and infection. Excessive extracellular matrix and adhesions contract pouches, bursae and tendons, cause pain and prevent a normal range of joint motion, with devastating consequences for patient quality of life. Arthrofibrosis affects people of all ages, with published rates varying. The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers. However, current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis. The process begins when stress signals stimulate immune cells. The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts, which secrete fibrillar collagens and transforming growth factor-β (TGF-β). Positive feedback networks then dysregulate processes that normally terminate healing processes. We propose two subtypes of arthrofibrosis occur: active arthrofibrosis and residual arthrofibrosis. In the latter the fibrogenic processes have resolved but the joint remains stiff. The best therapeutic approach for each subtype may differ significantly. Treatment typically involves surgery, however, a pharmacological approach to correct dysregulated cell signalling could be more effective. Recent research shows that myofibroblasts are capable of reversing differentiation, and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments. Therapies with significant promise are currently available, with more in development, including those that inhibit TGF-β signalling and epigenetic modifications. This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments.
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Affiliation(s)
- Kayley M. Usher
- School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia Australia
| | - Sipin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang China
| | - Georgios Mavropalias
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia Australia
| | | | - Jinmin Zhao
- Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi China
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi China
| | - Jiake Xu
- School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia Australia
- Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi China
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23
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He B, Fu GH, Du XF, Chu HM. Halofuginone protects HUVECs from H2O2-induced injury by modulating VEGF/JNK signaling pathway. J Chin Med Assoc 2019; 82:92-98. [PMID: 30839497 DOI: 10.1097/jcma.0000000000000008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Halofuginone, which is the main active ingredient of Dichroa fabrifuga, was used to inhibit the synthesis of type I collagen and played increasingly important roles in tumor therapy. This study aims to investigate the protective effects of halofuginone on human umbilical vein endothelial cells (HUVECs) from H2O2-induced apoptosis and oxidative stress. METHODS Propidium iodide and Annexin-V double staining assay was used to measure the apoptosis. Cell viability assay, the measurements of reactive oxygen species (ROS) parameters malondialdehyde and superoxide dismutase, western-blot assays, and quantitative PCR were used to elucidate the effects and mechanisms of halofuginone in protecting H2O2-induced injury. RESULTS The results showed that halofuginone counteracted H2O2-induced cell viability decline and PCNA downregulation. Furthermore, halofuginone decreased ROS levels and protected HUVECs from H2O2-induced apoptosis. In detail, it showed that H2O2 induced a transient activation of Mitogen-activated protein kinases members ERK1/2 and p38, whereas induced a sustained activation of c-Jun N-terminal kinase (JNK), which play dominant roles in triggering apoptosis. Inhibition of JNK activation also inhibited H2O2-mediated apoptosis. Finally, it was shown that halofuginone upregulated VEGF expressions, which functioned by inhibiting sustained JNK activation, thus protecting HUVECs. CONCLUSION Halofuginone has powerful effects in protecting HUVECs from H2O2-induced apoptosis, via upregulating VEGF and inhibiting overactivated JNK phosphorylation. Halofuginone might be a promising preventive drug for cardiovascular diseases.
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Affiliation(s)
- Bin He
- Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang, China
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24
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Ebrahimi H, Naderian M, Sohrabpour AA. New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article. Middle East J Dig Dis 2018; 10:133-148. [PMID: 30186577 PMCID: PMC6119836 DOI: 10.15171/mejdd.2018.103] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
Currently, liver fibrosis and its complications are regarded as critical health problems.
With the studies showing the reversible nature of liver fibrogenesis, scientists have focused
on understanding the underlying mechanism of this condition in order to develop new
therapeutic strategies. Although hepatic stellate cells are known as the primary cells
responsible for liver fibrogenesis, studies have shown contributing roles for other cells,
pathways, and molecules in the development of fibrosis depending on the etiology of
liver fibrosis. Hence, interventions could be directed in the proper way for each type of
liver diseases to better address this complication. There are two main approaches in clinical
reversion of liver fibrosis; eliminating the underlying insult and targeting the fibrosis
process, which have variable clinical importance in the treatment of this disease. In this
review, we present recent concepts in molecular pathways of liver fibrosis reversibility
and their clinical implications.
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Affiliation(s)
- Hedyeh Ebrahimi
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Naderian
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Sohrabpour
- Associate Professor, The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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25
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Cerit KK, Karakoyun B, Bahadır E, Yüksel M, Bülbül N, Ercan F, Dağlı ET, Yeğen BÇ. Halofuginone improves caustic-induced oxidative injury of esophagus in rats. Esophagus 2018; 15:59-68. [PMID: 29892928 DOI: 10.1007/s10388-017-0594-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 09/27/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND The aim of this study is to evaluate the anti-inflammatory and anti-fibrotic effects of halofuginone in caustic esophageal burn injury in rats. MATERIALS AND METHODS Corrosive esophageal injury (CEI) was produced in male Wistar albino rats by instilling NaOH solution (1 ml, 37.5%) into the distal esophagus. Rats were decapitated on the 3rd day (early group) or 28th day (late group), and treated daily with either saline or halofuginone (100 µg/kg/day; i.p.), continued on alternate days after the third day. Histopathological evaluation and measurement of nitric oxide (NO), peroxynitrite (ONOO-) and oxygen-derived radicals by chemiluminescence (CL) were made in the distal 2 cm of the esophagus. Non-irrigated proximal esophageal samples were assessed for the levels of nuclear factor (NF)-κB, caspase-3, glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) activity. RESULTS GSH, MDA, NF-κB and caspase-3 levels, and MPO activity in the proximal esophagus were not different among groups. Increased number of TUNEL (+) cells in the irrigated esophagus of the early and late caustic injury groups was reduced by halofuginone treatment. High microscopic damage scores in both early and late CEI groups were decreased with halofuginone treatment. NO, ONOO- and CL levels, which were elevated in the saline-treated early CEI group, were reduced by halofuginone treatment, but reduced NO and ONOO- levels in the late period of saline-treated group were increased by halofuginone. CONCLUSION In addition to its anti-fibrotic effects, current findings demonstrate that halofuginone exerts antioxidant and anti-apoptotic actions and supports therapeutic potential for halofuginone in CEI-induced oxidative stress.
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Affiliation(s)
- Kıvılcım Karadeniz Cerit
- Department of Pediatric Surgery, School of Medicine, Marmara University, Fevzi Çakmak Mahallesi, Muhsin Yazicioğlu Caddesi, No: 10, Üst Kaynarca, Pendik, 34899, Istanbul, Turkey.
| | - Berna Karakoyun
- Department of Basic Health Sciences, Marmara University Health Sciences Faculty, Istanbul, Turkey
| | - Elif Bahadır
- Department of Physiology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Meral Yüksel
- Department of Medical Laboratory, Marmara University Vocational School of Health Related Professions, Istanbul, Turkey
| | - Nurdan Bülbül
- Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Feriha Ercan
- Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkey
| | - E Tolga Dağlı
- Department of Pediatric Surgery, School of Medicine, Marmara University, Fevzi Çakmak Mahallesi, Muhsin Yazicioğlu Caddesi, No: 10, Üst Kaynarca, Pendik, 34899, Istanbul, Turkey
| | - Berrak Ç Yeğen
- Department of Physiology, School of Medicine, Marmara University, Istanbul, Turkey
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26
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Mu W, Xu B, Ma H, Li J, Ji B, Zhang Z, Amat A, Cao L. Halofuginone Attenuates Osteoarthritis by Rescuing Bone Remodeling in Subchondral Bone Through Oral Gavage. Front Pharmacol 2018; 9:269. [PMID: 29636687 PMCID: PMC5881118 DOI: 10.3389/fphar.2018.00269] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 03/09/2018] [Indexed: 12/13/2022] Open
Abstract
Osteoarthritis (OA) is a common debilitating joint disorder worldwide without effective medical therapy. Articular cartilage and subchondral bone act in concert as a functional unit with the onset of OA. Halofuginone is an analog of the alkaloid febrifugine extracted from the plant Dichroa febrifuga, which has been demonstrated to exert inhibition of SMAD 2/3 phosphorylation downstream of the TGF-β signaling pathway and osteoclastogenesis. To investigate whether halofuginone (HF) alleviates OA after administration by oral gavage, 3-month-old male mice were allocated to the Sham group, vehicle-treated anterior cruciate ligament transection (ACLT) group, and HF-treated ACLT group. The immunostaining analysis indicated that HF reduced the number of matrix metalloproteinase 13 (MMP-13) and collagen X (Col X) positive cells in the articular cartilage. Moreover, HF lowered histologic OA score and prevented articular cartilage degeneration. The micro-computed tomography (μCT) scan showed that HF maintained the subchondral bone microarchitecture, demonstrated by the restoration of bone volume fraction (BV/TV), subchondral bone plate thickness (SBP.Th.), and trabecular pattern factor (Tb.Pf) to a level comparable to that of the Sham group. Immunostaining for CD31 and μCT based angiography showed that the number and volume of vessels in subchondral bone was restored by HF. HF administered by oral gavage recoupled bone remodeling and inhibited aberrant angiogenesis in the subchondral bone, further slowed the progression of OA. Therefore, HF administered by oral gavage could be a potential therapy for OA.
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Affiliation(s)
- Wenbo Mu
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Boyong Xu
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Hairong Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian Xinjiang Key Laboratory of Echinococcosis, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Jiao Li
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Baochao Ji
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Zhendong Zhang
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Abdusami Amat
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Li Cao
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
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27
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Luo L, Gao Y, Yang C, Shao Z, Wu X, Li S, Xiong L, Chen C. Halofuginone attenuates intervertebral discs degeneration by suppressing collagen I production and inactivating TGFβ and NF-кB pathway. Biomed Pharmacother 2018. [PMID: 29524883 DOI: 10.1016/j.biopha.2018.01.100] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Most low back pain is caused by intervertebral discs (IVD) degeneration, a disease that prevalence is increasing with age. Halofuginone, an analog of ferbrifugine isolated from plant Dichroa febrifuga, has drawn much attention in recent years for the wide range of bioactivities in malaria, cancer, fibrotic and autoimmune diseases. In this study, we evaluated the benefit effects of halofuginone in IVD degeneration treatment in a validated rabbit puncture model. Halofuginone treatment could attenuate disc degeneration by suppressing the decrease of discs height and nucleus pulposus signal strength. Besides, halofuginone treatment could suppress mRNA and protein expression of collagen I in nucleus pulposus. This might possibly due to the inactivation of transform growth factor-β (TGFβ) signal pathway by down-regulating p-Samd3 and up-regulating inhibitory Smad7. Then, we evaluated the effects of halofuginone treatment on nuclear factor of kappa B (NF-κB) signal pathway and its downstream pro-inflammatory cytokines. The level of p-p65 and p-IκBα was down-regulated in halofuginone treated group, indicating the inactivation of NF-κB signal pathway. The mRNA expression of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 8 (IL-8) was decreased in nucleus pulposus too, indicating the down-regulation of pro-inflammatory cytokines. In conclusion, halofuginone treatment could attenuate IVD degeneration and this was possibly due to suppressing of collagen I production and inactivation of TGFβ and NF-κB signal pathway in nucleus pulposus of degenerated discs. These results suggest that halofuginone has the potential for IVD degeneration treatment, but more research is needed to validate this.
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Affiliation(s)
- Linghui Luo
- Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yong Gao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shuai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Liming Xiong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chao Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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28
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Mu W, Xu B, Ma H, Ji B, Zhang Z, Li J, Amat A, Cao L. Halofuginone attenuates articular cartilage degeneration by inhibition of elevated TGF‑β1 signaling in articular cartilage in a rodent osteoarthritis model. Mol Med Rep 2017; 16:7679-7684. [PMID: 28944864 DOI: 10.3892/mmr.2017.7549] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 08/14/2017] [Indexed: 11/05/2022] Open
Abstract
Osteoarthritis (OA) is the most common degenerative condition of the weight‑bearing joints worldwide without effective medical therapy. In order to investigate whether administration of halofuginone (HF) may attenuate OA, the present study allocated 3‑month‑old male mice into Sham group, vehicle‑treated anterior cruciate ligament transection (ACLT) group and HF‑treated ACLT group. The present study determined that HF treatment reduced the expression of matrix metallopeptidase‑13 and collagen X in articular cartilage. Additionally, it lowered the Osteoarthritis Research Society International‑Modified Mankin score and prevented the loss of articular cartilage from Safranin O and Fast Green staining. HF reduced the progression of osteoarthritis by downregulating abnormally elevated TGF‑β1 activity in articular cartilage. Administration of HF may be a potential preventive therapy for OA.
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Affiliation(s)
- Wenbo Mu
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Boyong Xu
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Hairong Ma
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Baochao Ji
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Zhendong Zhang
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Jiao Li
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Abdusami Amat
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Li Cao
- Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
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29
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A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide. Molecules 2017; 22:molecules22071086. [PMID: 28665346 PMCID: PMC6152095 DOI: 10.3390/molecules22071086] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 06/28/2017] [Accepted: 06/28/2017] [Indexed: 12/12/2022] Open
Abstract
Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and 1H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production.
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Elevated Expression of Moesin in Muscular Dystrophies. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:654-664. [PMID: 28082118 DOI: 10.1016/j.ajpath.2016.11.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 10/30/2016] [Accepted: 11/15/2016] [Indexed: 12/27/2022]
Abstract
Fibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin-positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials.
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Longchamp A, Harputlugil E, Corpataux JM, Ozaki CK, Mitchell JR. Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review. Gerontology 2017; 63:228-237. [PMID: 28052287 DOI: 10.1159/000453109] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 11/07/2016] [Indexed: 12/15/2022] Open
Abstract
Dietary restriction (DR) is best known for extending lifespan in experimental model organisms, but also increases resistance to a variety of clinically relevant stressors, including those associated with surgery. Extended periods of DR, lasting months to years, are required for optimal longevity benefits in rodents, but short-term dietary preconditioning (less than 1 week) remarkably protects from acute injury. Here, we discuss recent advances in our understanding of the mechanistic basis of short-term DR and fasting in the context of surgical stress resistance, including upstream amino acid sensing by the GCN2 and mTORC1 pathways, and downstream effector mechanisms including increased insulin-dependent prosurvival signaling and elevated endogenous hydrogen sulfide production. We also review the current trend in preoperative nutrition away from preoperative fasting and towards carbohydrate loading. Finally, we discuss the rationale for the nonmutually exclusive use of brief DR or pharmacological DR mimetics to precondition against the stress and potential complications of surgery.
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Affiliation(s)
- Alban Longchamp
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Abstract
Halofuginone is an analog of febrifugine-an alkaloid originally isolated from the plant Dichroa febrifuga. During recent years, halofuginone has attracted much attention because of its wide range of beneficial biological activities, which encompass malaria, cancer, and fibrosis-related and autoimmune diseases. At present two modes of halofuginone actions have been described: (1) Inhibition of Smad3 phosphorylation downstream of the TGFβ signaling pathway results in inhibition of fibroblasts-to-myofibroblasts transition and fibrosis. (2) Inhibition of prolyl-tRNA synthetase (ProRS) activity in the blood stage of malaria and inhibition of Th17 cell differentiation thereby inhibiting inflammation and the autoimmune reaction by activation of the amino acid starvation and integrated stress responses. This review deals with the history and origin of this natural product, its synthesis, its known modes of action, and it's various biological activities in pre-clinical animal models and in humans.
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Affiliation(s)
- Mark Pines
- The Volcani Center, Institute of Animal Science, P.O. Box 6, Bet Dagan 50250, Israel.
| | - Itai Spector
- The Volcani Center, Institute of Animal Science, P.O. Box 6, Bet Dagan 50250, Israel.
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