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Rutkowski K, Gola M, Godlewski J, Starzyńska A, Marvaso G, Mastroleo F, Giulia Vincini M, Porazzi A, Zaffaroni M, Jereczek-Fossa BA. Understanding the role of nerves in head and neck cancers - a review. Oncol Rev 2025; 18:1514004. [PMID: 39906323 PMCID: PMC11791411 DOI: 10.3389/or.2024.1514004] [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: 10/19/2024] [Accepted: 12/03/2024] [Indexed: 02/06/2025] Open
Abstract
Worldwide, head and neck cancers (HNCs) account for approximately 900,000 cases and 500,000 deaths annually, with their incidence continuing to rise. Carcinogenesis is a complex, multidimensional molecular process leading to cancer development, and in recent years, the role of nerves in the pathogenesis of various malignancies has been increasingly recognized. Thanks to the abundant innervation of the head and neck region, peripheral nervous system has gained considerable interest for its possible role in the development and progression of HNCs. Intratumoral parasympathetic, sympathetic, and sensory nerve fibers are emerging as key players and potential targets for novel anti-cancer and pain-relieving medications in different tumors, including HNCs. This review explores nerve-cancer interactions, including perineural invasion (PNI), cancer-related axonogenesis, neurogenesis, and nerve reprogramming, with an emphasis on their molecular mechanisms, mediators and clinical implications. PNI, an adverse histopathologic feature, has been widely investigated in HNCs. However, its prognostic value remains debated due to inconsistent results when classified dichotomously (present/absent). Emerging evidence suggests that quantitative and qualitative descriptions of PNI may better reflect its clinical usefulness. The review also examines therapies targeting nerve-cancer crosstalk and highlights the influence of HPV status on tumor innervation. By synthesizing current knowledge, challenges, and future perspectives, this review offers insights into the molecular basis of nerve involvement in HNCs and the potential for novel therapeutic approaches.
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Affiliation(s)
- Krzysztof Rutkowski
- Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Michał Gola
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
- Department of Oncology and Immuno-Oncology, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, Olsztyn, Poland
| | - Janusz Godlewski
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
- Department of Surgical Oncology, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, Olsztyn, Poland
| | - Anna Starzyńska
- Department of Oral Surgery, Medical University of Gdańsk, Gdańsk, Poland
- Department of Otolaryngology, Phoniatrics and Audiology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Giulia Marvaso
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Federico Mastroleo
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Maria Giulia Vincini
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Alice Porazzi
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Mattia Zaffaroni
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Barbara Alicja Jereczek-Fossa
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Zheng S, Qi W, Xue T, Zao X, Xie J, Zhang P, Li X, Ye Y, Liu A. Chinese medicine in the treatment of chronic hepatitis B: The mechanisms of signal pathway regulation. Heliyon 2024; 10:e39176. [PMID: 39640799 PMCID: PMC11620126 DOI: 10.1016/j.heliyon.2024.e39176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 10/08/2024] [Indexed: 12/07/2024] Open
Abstract
Chronic hepatitis B (CHB) is a chronic inflammatory disease of the liver caused by infection with the hepatitis B virus (HBV), which in later stages can lead to the development of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma in severe cases, jeopardizing long-term quality of life, with a poor prognosis, and placing a serious financial burden on many families around the world. The pathogenesis of the disease is complex and closely related to the immune function of the body, which has not yet been fully elucidated. The development of chronic hepatitis B is closely related to the involvement of various signaling pathways, such as JAK/STAT, PI3K/Akt, Toll-like receptor, NF-κB and MAPK signaling pathways. A large number of studies have shown that Chinese medicine has obvious advantages in anti-hepatitis B virus, and it can effectively treat the disease by modulating relevant signaling pathways, strengthening immune resistance and defense, and inhibiting inflammatory responses, and certain research progress has been made, but there is still a lack of a comprehensive review on the modulation of relevant signaling pathways in Chinese medicine for the treatment of CHB. Therefore, this article systematically combed and elaborated the relevant literature on the modulation of relevant signaling pathways by traditional Chinese medicine in recent years, with a view to providing new ideas for the treatment of CHB and further drug development.
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Affiliation(s)
- Shihao Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Wenying Qi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Tianyu Xue
- Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang, 050000, China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
| | - Jinchi Xie
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Peng Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yongan Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Aimin Liu
- Shangzhuang Township Community Health Service Center, Beijing, 100094, China
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3
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Gocol H, Zeng JH, Chang S, Koh BY, Nguyen H, Cirillo N. A Critical Interpretive Synthesis of the Role of Arecoline in Oral Carcinogenesis: Is the Local Cholinergic Axis a Missing Link in Disease Pathophysiology? Pharmaceuticals (Basel) 2023; 16:1684. [PMID: 38139811 PMCID: PMC10748297 DOI: 10.3390/ph16121684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/24/2023] Open
Abstract
Arecoline is the primary active carcinogen found in areca nut and has been implicated in the pathogenesis of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). For this study, we conducted a stepwise review process by combining iterative scoping reviews with a post hoc search, with the aim of identifying the specific mechanisms by which arecoline initiates and promotes oral carcinogenesis. Our initial search allowed us to define the current trends and patterns in the pathophysiology of arecoline-induced OSF and OSCC, which include the induction of cell proliferation, facilitation of invasion, adhesion, and migration, increased collagen deposition and fibrosis, imbalance in immune and inflammatory mechanisms, and genotoxicity. Key molecular pathways comprise the activation of NOTCH1, MYC, PRDX2, WNT, CYR61, EGFR/Pl3K, DDR1 signaling, and cytokine upregulation. Despite providing a comprehensive overview of potential pathogenic mechanisms of OSF, the involvement of molecules functioning as areca alkaloid receptors, namely, the muscarinic and nicotinic acetylcholine receptors (AChRs), was not elucidated with this approach. Accordingly, our search strategy was refined to reflect these evidence gaps. The results of the second round of reviews with the post hoc search highlighted that arecoline binds preferentially to muscarinic AChRs, which have been implicated in cancer. Consistently, AChRs activate the signaling pathways that partially overlap with those described in the context of arecoline-induced carcinogenesis. In summary, we used a theory-driven interpretive review methodology to inform, extend, and supplement the conventional systematic literature assessment workflow. On the one hand, the results of this critical interpretive synthesis highlighted the prevailing trends and enabled the consolidation of data pertaining to the molecular mechanisms involved in arecoline-induced carcinogenesis, and, on the other, brought up knowledge gaps related to the role of the local cholinergic axis in oral carcinogenesis, thus suggesting areas for further investigation.
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Affiliation(s)
| | | | | | | | | | - Nicola Cirillo
- Melbourne Dental School, The University of Melbourne, Carlton, VIC 3053, Australia (B.Y.K.)
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Auschwitz E, Almeda J, Andl CD. Mechanisms of E-Cigarette Vape-Induced Epithelial Cell Damage. Cells 2023; 12:2552. [PMID: 37947630 PMCID: PMC10650279 DOI: 10.3390/cells12212552] [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: 07/25/2023] [Revised: 10/24/2023] [Accepted: 10/28/2023] [Indexed: 11/12/2023] Open
Abstract
E-cigarette use has been reported to affect cell viability, induce DNA damage, and modulate an inflammatory response resulting in negative health consequences. Most studies focus on oral and lung disease associated with e-cigarette use. However, tissue damage can be found in the cardio-vascular system and even the bladder. While the levels of carcinogenic compounds found in e-cigarette aerosols are lower than those in conventional cigarette smoke, the toxicants generated by the heat of the vaping device may include probable human carcinogens. Furthermore, nicotine, although not a carcinogen, can be metabolized to nitrosamines. Nitrosamines are known carcinogens and have been shown to be present in the saliva of e-cig users, demonstrating the health risk of e-cigarette vaping. E-cig vape can induce DNA adducts, promoting oxidative stress and DNA damage and NF-kB-driven inflammation. Together, these processes increase the transcription of pro-inflammatory cytokines. This creates a microenvironment thought to play a key role in tumorigenesis, although it is too early to know the long-term effects of vaping. This review considers different aspects of e-cigarette-induced cellular changes, including the generation of reactive oxygen species, DNA damage, DNA repair, inflammation, and the possible tumorigenic effects.
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Affiliation(s)
| | | | - Claudia D. Andl
- Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32816, USA
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Kim SH, Lee SE, Kim SJ, Fang X, Hur J, Sozen E, Özer NK, Kim KP, Surh YJ. Protective effects of an electrophilic metabolite of docosahexaenoic acid on UVB-induced oxidative cell death, dermatitis, and carcinogenesis. Redox Biol 2023; 62:102666. [PMID: 36934646 PMCID: PMC10031545 DOI: 10.1016/j.redox.2023.102666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/04/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
Docosahexaenoic acid (DHA), a representative omega-3 (ω-3) polyunsaturated fatty acids, undergoes metabolism to produce biologically active electrophilic species. 17-Oxo-DHA is one such reactive metabolite generated from DHA by cyclooxygenase-2 and dehydrogenase in activated macrophages. The present study was aimed to investigate the effects of 17-oxo-DHA on ultraviolet B (UVB)-induced oxidative stress, inflammation, and carcinogenesis in mouse skin. UVB-induced epidermal cell death was ameliorated by topically applied 17-oxo-DHA. Topical application of 17-oxo-DHA onto hairless mouse skin inhibited UVB-induced phosphorylation of the proinflammatory transcription factor, STAT3 on tyrosine 705 (Tyr705). The 17-oxo-DHA treatment also reduced the levels of oxidative stress markers, 4-hydroxynonenal-modified protein, malondialdehyde, and 8-oxo-2'-deoxyguanosine. The protective effects of 17-oxo-DHA against oxidative damage in UVB-irradiated mouse skin were associated with activation of Nrf2. 17-Oxo-DHA enhanced the engulfment of apoptotic JB6 cells by macrophages, which was related to the increased expression of the scavenger receptor CD36. The 17-oxo-DHA-mediated potentiation of efferocytic activity of macrophages was attenuated by the pharmacologic inhibition or knockout of Nrf2. The pretreatment with 17-oxo-DHA reduced the UVB-induced skin carcinogenesis and tumor angiogenesis. It was also confirmed that 17-oxo-DHA treatment significantly inhibited the phosphorylation of the Tyr705 residue of STAT3 and decreased the expression of its target proteins in cutaneous papilloma. In conclusion, 17-oxo-DHA protects against UVB-induced oxidative cell death, dermatitis, and carcinogenesis. These effects were associated with inhibition of STAT3-mediated proinflammatory signaling and also activation of Nrf2 with subsequent upregulation of antioxidant and anti-inflammatory gene expression.
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Affiliation(s)
- Seong Hoon Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - So Eui Lee
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Su-Jung Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Xizhu Fang
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Jihyeon Hur
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, South Korea
| | - Erdi Sozen
- Department of Biochemistry, Faculty of Medicine, Marmara University, Maltepe, Istanbul, Turkey
| | - Nesrin Kartal Özer
- Department of Biochemistry, Faculty of Medicine, Uskudar University, Altunizade, Istanbul, Turkey
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, South Korea; Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, South Korea.
| | - Young-Joon Surh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea.
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6
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Zhang C, Li M, Xie W, Li M, You C, Wang T, Fu F. Administration of Huperzine A microspheres ameliorates myocardial ischemic injury via α7nAChR-dependent JAK2/STAT3 signaling pathway. Eur J Pharmacol 2023; 940:175478. [PMID: 36563953 DOI: 10.1016/j.ejphar.2022.175478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 12/17/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Acetylcholinesterase (AChE) inhibitor (AChEI) is well established as first-line agents for relieving the symptoms of Alzheimer's disease (AD). Injectable sustained-release formulation of AChEI may be suitable for treating AD patients. However, it needs to know whether continuous inhibition of AChE could deteriorate or attenuate myocardial damage if myocardial ischemia (MI) occurs. Huperzine A microspheres (HAM) are a sustained-release formulation releasing sustainably huperzine A (an AChEI) for more than 7 days after a single dose of HAM. This study aimed to investigate the myocardial damage in an isoprenaline (ISO)-induced MI mice model during HAM treatment. The heart injury was evaluated by assaying serum CK-MB, Tn-I and observing histopathological changes. The levels of proinflammatory cytokines in serum were detected. The level of p-P65 and the expression of proteins in the JAK2/STAT3 signaling pathway were assayed with Western blot. Administration with a single dose of HAM resulted in inhibiting the MI-induced increases of CK-MB and Tn-I, alleviating the damage of heart tissue, and decreasing the levels of TNF-α and IL-6. In addition, HAM decreased the levels of p-P65, p-JAK2, and p-STAT3 in heart tissue. The effects of HAM could be weakened or abolished by the specific α7nAChR antagonist. These findings suggest that continuous AChE inhibition could protect the heart from ischemic damage during administration of sustained-release formulation of AChEI, which is associated with the anti-inflammatory effect of HAM by regulating α7nAChR-dependent JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Ce Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, PR China
| | - Mingan Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, PR China
| | - Wei Xie
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, PR China
| | - Min Li
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250355, PR China
| | - Chunna You
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, PR China
| | - Tian Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, PR China.
| | - Fenghua Fu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, PR China.
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7
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Khatoon E, Hegde M, Kumar A, Daimary UD, Sethi G, Bishayee A, Kunnumakkara AB. The multifaceted role of STAT3 pathway and its implication as a potential therapeutic target in oral cancer. Arch Pharm Res 2022; 45:507-534. [PMID: 35987863 DOI: 10.1007/s12272-022-01398-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 07/20/2022] [Indexed: 12/20/2022]
Abstract
Oral cancer is one of the leading causes of cancer-related deaths, and it has become a matter of serious concern due to the alarming rise in its incidence rate worldwide. Despite recent advancements in oral cancer treatment strategies, there are no significant improvements in patient's survival rate. Among the numerous cell signaling pathways involved in oral cancer development and progression, STAT3 is known to play a multifaceted oncogenic role in shaping the tumor pathophysiology. STAT3 hyperactivation in oral cancer contributes to survival, proliferation, invasion, epithelial to mesenchymal transition, metastasis, immunosuppression, chemoresistance, and poor prognosis. A plethora of pre-clinical and clinical studies have documented the role of STAT3 in the initiation and development of oral cancer and showed that STAT3 inhibition holds significant potential in the prevention and treatment of this cancer. However, to date, targeting STAT3 activation mainly involves inhibiting the upstream signaling molecules such as JAK and IL-6 receptors. The major challenge in targeting STAT3 lies in the complexity of its phosphorylation- and dimerization-independent functions, which are not affected by disrupting the upstream regulators. The present review delineates the significance of the STAT3 pathway in regulating various hallmarks of oral cancer. In addition, it highlights the STAT3 inhibitors identified to date through various preclinical and clinical studies that can be employed for the therapeutic intervention in oral cancer treatment.
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Affiliation(s)
- Elina Khatoon
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India. .,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.
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8
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Khodabandeh Z, Valilo M, Velaei K, Pirpour Tazehkand A. The potential role of nicotine in breast cancer initiation, development, angiogenesis, invasion, metastasis, and resistance to therapy. Breast Cancer 2022; 29:778-789. [PMID: 35583594 DOI: 10.1007/s12282-022-01369-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/27/2022] [Indexed: 01/03/2023]
Abstract
A large body of research studying the relationship between tobacco and cancer has led to the knowledge that smoking cigarettes adversely affects cancer treatment while contributing to the development of various tobacco-related cancers. Nicotine is the main addictive component of tobacco smoke and promotes angiogenesis, proliferation, and epithelial-mesenchymal transition (EMT) while promoting growth and metastasis of tumors. Nicotine generally acts through the induction of the nicotinic acetylcholine receptors (nAChRs), although the contribution of other receptor subunits has also been reported. Nicotine contributes to the pathogenesis of a wide range of cancers including breast cancer through its carcinogens such as (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN). Current study aims to review the mechanistic function of nicotine in the initiation, development, angiogenesis, invasion, metastasis, and apoptosis of breast cancer with the main focus on nicotine acetylcholine receptors (nAChRs) and nAChR-mediated signaling pathways as well as on its potential for the development of an effective treatment against breast cancer. Moreover, we will try to demonstrate how nicotine leads to poor treatment response in breast cancer by enhancing the population, proliferation, and self-renewal of cancer stem cells (CSCs) through the activation of α7-nAChR receptors.
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Affiliation(s)
- Zhila Khodabandeh
- Department of Biology, Faculty of Science, Urmia University, Urmia, Iran
| | - Mohammad Valilo
- Department of Clinical Biochemistry and Medical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kobra Velaei
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Abbas Pirpour Tazehkand
- Department of Clinical Biochemistry and Medical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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9
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Danesh Pouya F, Rasmi Y, Nemati M. Signaling Pathways Involved in 5-FU Drug Resistance in Cancer. Cancer Invest 2022; 40:516-543. [PMID: 35320055 DOI: 10.1080/07357907.2022.2055050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Anti-metabolite drugs prevent the synthesis of essential cell growth compounds. 5-fluorouracil is used as an anti-metabolic drug in various cancers in the first stage of treatment. Unfortunately, in some cancers, 5-fluorouracil has low effectiveness because of its drug resistance. Studies have shown that drug resistance to 5-fluorouracil is due to the activation of specific signaling pathways and increased expressions of enzymes involved in drug metabolites. However, when 5-fluorouracil is used in combination with other drugs, the sensitivity of cancer cells to 5-fluorouracil increases, and the effect of drug resistance is reversed. This study discusses how the function of 5-fluorouracil in JAK/STAT, Wnt, Notch, NF-κB, and hedgehogs in some cancers.
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Affiliation(s)
- Fahima Danesh Pouya
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohadeseh Nemati
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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10
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Zhang Q, Jia Y, Pan P, Zhang X, Jia Y, Zhu P, Chen X, Jiao Y, Kang G, Zhang L, Ma X. α5-nAChR associated with Ly6E modulates cell migration via TGF-β1/Smad signaling in non-small cell lung cancer. Carcinogenesis 2022; 43:393-404. [PMID: 34994389 DOI: 10.1093/carcin/bgac003] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/21/2021] [Accepted: 01/04/2022] [Indexed: 11/13/2022] Open
Abstract
The α5-nicotinic acetylcholine receptor (α5-nAChR) is closely associated with nicotine-related lung cancer, offering a novel perspective for investigating the molecular pathogenesis of this disease. However, the mechanism by which α5-nAChR functions in lung carcinogenesis remains to be elucidated. Lymphocyte antigen 6 (Ly6) proteins, like snake three-finger alpha toxins such as α-bungarotoxin, can modulate nAChR signaling. Ly6E, a member of the Ly6 family, is a biomarker of poor prognosis in smoking-induced lung carcinogenesis and is involved in the regulation of TGF-β1/Smad signaling. Here, we explored the underlying mechanisms linking α5-nAChR and Ly6E in non-small cell lung cancer (NSCLC). The expression of α5-nAChR was correlated with Ly6 expression, smoking status and lower survival in NSCLC tissues. In vitro, α5-nAChR mediated Ly6E, the phosphorylation of the TGF-β1 downstream molecule Smad3 (pSmad3, a key mediator of TGF-β1 signaling), the epithelial-mesenchymal transition (EMT) markers Zeb1, N-cadherin and vimentin expression in NSCLC cells. The downregulation of Ly6E reduced α5-nAChR, pSmad3, Zeb1, N-cadherin and vimentin expression. Functionally, silencing both α5-nAChR and Ly6E significantly inhibited cell migration compared to silencing α5-nAChR or Ly6E alone. Furthermore, the functional effects of α5-nAchR and Ly6E were confirmed in chicken embryo chorioallantoic membrane (CAM) and mouse xenograft models. Therefore, our findings uncover a new interaction between α5-nAChR and Ly6E that inhibits cancer cell migration by modulating the TGF-β1/Smad signaling pathway in NSCLC, which may serve as a novel target for therapeutic intervention.
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Affiliation(s)
- Qian Zhang
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Jia
- Department of Clinical Laboratory, Taian City Central Hospital, Taian, China
| | - Pan Pan
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiuping Zhang
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yanfei Jia
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ping Zhu
- Department of Medical Laboratory, Weifang Medical University, Weifang, China
| | - Xiaowei Chen
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yang Jiao
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guiyu Kang
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Clinical Laboratory, Taian City Central Hospital, Taian, China
| | - Lulu Zhang
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoli Ma
- Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Medical Laboratory, Weifang Medical University, Weifang, China.,Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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11
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Stegemann A, Raker V, Del Rey A, Steinbrink K, Böhm M. Expression of the α7 Nicotinic Acetylcholine Receptor Is Critically Required for the Antifibrotic Effect of PHA-543613 on Skin Fibrosis. Neuroendocrinology 2022; 112:446-456. [PMID: 34120115 DOI: 10.1159/000517772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/09/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Targeting the α7 nicotinic acetylcholine receptor (α7nAChR) has recently been suggested as a potential new treatment for fibrotic skin diseases. Here, we performed a genetic and pharmacologic approach to clarify the role of this receptor in the bleomycin (BLM) mouse model of skin fibrosis using α7nAChR KO mice. METHODS We analyzed the expression of extracellular matrix (ECM) components in murine skin using quantitative RT-PCR, pepsin digestion/SDS-PAGE of proteins and performed hydroxyproline assays as well as histological/immunohistochemical staining of skin sections. To identity the target cells of the α7nAChR agonist PHA-543613, we used murine dermal fibroblasts (MDF). We tested their response to the profibrotic cytokine transforming growth factor-β1 (TGF-β1) and utilized gene silencing to elucidate the role of the α7nAChR. RESULTS We confirmed our previous findings on C3H/HeJ mice and detected a suppressive effect of PHA-543613 on BLM-induced skin fibrosis in the mouse strain C57BL/6J. This antifibrotic effect of PHA-543613 was abrogated in α7nAChR-KO mice. Interestingly, α7nAChR-KO animals exhibited a basal profibrotic signature by higher RNA expression of ECM genes and hydroxyproline content than WT mice. In WT MDF, PHA-543613 suppressed ECM gene expression induced by TGF-β1. Gene silencing of α7nAChR by small interfering RNA neutralized the effects of PHA-543613 on TGF-β1-mediated ECM gene expression. CONCLUSION In summary, we have identified the α7nAChR as the essential mediator of the antifibrotic effect of PHA-543613. MDF are directly targeted by PHA-543613 to suppress collagen synthesis. Our findings emphasize therapeutic exploitation of α7nAChR receptor agonists in fibrotic skin diseases.
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Affiliation(s)
- Agatha Stegemann
- Department of Dermatology, University of Münster, Münster, Germany
| | - Verena Raker
- Department of Dermatology, University of Münster, Münster, Germany
- Department of Dermatology, University of Mainz, Mainz, Germany
| | - Adriana Del Rey
- Institute for Physiology and Pathophysiology, University of Marburg, Marburg, Germany
| | | | - Markus Böhm
- Department of Dermatology, University of Münster, Münster, Germany
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12
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Veerappa A, Pendyala G, Guda C. A systems omics-based approach to decode substance use disorders and neuroadaptations. Neurosci Biobehav Rev 2021; 130:61-80. [PMID: 34411560 PMCID: PMC8511293 DOI: 10.1016/j.neubiorev.2021.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/23/2021] [Accepted: 08/14/2021] [Indexed: 11/15/2022]
Abstract
Substance use disorders (SUDs) are a group of neuropsychiatric conditions manifesting due to excessive dependence on potential drugs of abuse such as psychostimulants, opioids including prescription opioids, alcohol, inhalants, etc. Experimental studies have generated enormous data in the area of SUDs, but outcomes from such data have remained largely fragmented. In this review, we attempt to coalesce these data points providing an important first step towards our understanding of the etiology of SUDs. We propose and describe a 'core addictome' pathway that behaves central to all SUDs. Besides, we also have made some notable observations paving way for several hypotheses; MECP2 behaves as a master switch during substance use; five distinct gene clusters were identified based on respective substance addiction; a central cluster of genes serves as a hub of the addiction pathway connecting all other substance addiction clusters. In addition to describing these findings, we have emphasized the importance of some candidate genes that are of substantial interest for further investigation and serve as high-value targets for translational efforts.
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Affiliation(s)
- Avinash Veerappa
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Gurudutt Pendyala
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Center for Biomedical Informatics Research and Innovation, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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13
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Bychkov ML, Shulepko MA, Shlepova OV, Kulbatskii DS, Chulina IA, Paramonov AS, Baidakova LK, Azev VN, Koshelev SG, Kirpichnikov MP, Shenkarev ZO, Lyukmanova EN. SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer. Front Cell Dev Biol 2021; 9:739391. [PMID: 34595181 PMCID: PMC8476798 DOI: 10.3389/fcell.2021.739391] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 08/17/2021] [Indexed: 12/18/2022] Open
Abstract
Secreted Ly6/uPAR-related protein 1 (SLURP-1) is a secreted Ly6/uPAR protein that negatively modulates the nicotinic acetylcholine receptor of α7 type (α7-nAChR), participating in control of cancer cell growth. Previously we showed, that a recombinant analogue of human SLURP-1 (rSLURP-1) diminishes the lung adenocarcinoma A549 cell proliferation and abolishes the nicotine-induced growth stimulation. Here, using multiplex immunoassay, we demonstrated a decrease in PTEN and mammalian target of rapamycin (mTOR) kinase phosphorylation in A549 cells upon the rSLURP-1 treatment pointing on down-regulation of the PI3K/AKT/mTOR signaling pathway. Decreased phosphorylation of the platelet-derived growth factor receptor type β (PDGFRβ) and arrest of the A549 cell cycle in the S and G2/M phases without apoptosis induction was also observed. Using a scratch migration assay, inhibition of A549 cell migration under the rSLURP-1 treatment was found. Affinity extraction demonstrated that rSLURP-1 in A549 cells forms a complex not only with α7-nAChR, but also with PDGFRα and epidermal growth factor receptor (EGFR), which are known to be involved in regulation of cancer cell growth and migration and are able to form a heterodimer. Knock-down of the genes encoding α7-nAChR, PDGFRα, and EGFR confirmed the involvement of these receptors in the anti-migration effect of SLURP-1. Thus, SLURP-1 can target the α7-nAChR complexes with PDGFRα and EGFR in the membrane of epithelial cells. Using chimeric proteins with grafted SLURP-1 loops we demonstrated that loop I is the principal active site responsible for the SLURP-1 interaction with α7-nAChR and its antiproliferative effect. Synthetic peptide mimicking the loop I cyclized by a disulfide bond inhibited ACh-evoked current at α7-nAChR, as well as A549 cell proliferation and migration. This synthetic peptide represents a promising prototype of new antitumor drug with the properties close to that of the native SLURP-1 protein.
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Affiliation(s)
- Maxim L. Bychkov
- Bioengineering Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Mikhail A. Shulepko
- Bioengineering Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Olga V. Shlepova
- Bioengineering Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
- Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Dmitrii S. Kulbatskii
- Bioengineering Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Irina A. Chulina
- Group of Peptide Chemistry, Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Pushchino, Russia
| | - Alexander S. Paramonov
- Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Ludmila K. Baidakova
- Group of Peptide Chemistry, Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Pushchino, Russia
| | - Viatcheslav N. Azev
- Group of Peptide Chemistry, Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Pushchino, Russia
| | - Sergey G. Koshelev
- Department of Molecular Neurobiology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Mikhail P. Kirpichnikov
- Bioengineering Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
- Biological Faculty, Lomonosov Moscow State University, Moscow, Russia
| | - Zakhar O. Shenkarev
- Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
- Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Ekaterina N. Lyukmanova
- Bioengineering Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
- Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
- Biological Faculty, Lomonosov Moscow State University, Moscow, Russia
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14
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Sharma M, Shetty SS, Radhakrishnan R. Novel Pathways and Mechanism of Nicotine-Induced Oral Carcinogenesis. Recent Pat Anticancer Drug Discov 2021; 17:66-79. [PMID: 34365933 DOI: 10.2174/1574892816666210806161312] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine-derived Nitrosamines (NDNs). METHODS A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis. RESULTS Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR. CONCLUSION Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.
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Affiliation(s)
- Mohit Sharma
- Department of Oral Pathology, Sudha Rustagi College of Dental Sciences and Research, Faridabad - 121004. India
| | - Smitha S Shetty
- Department of Oral Pathology, Faculty of Dentistry, Melaka Manipal Medical College, Manipal, (Karnataka). India
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal - 576104. India
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15
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Wang Y, Xia YY, Xue M, Jiang Q, Huang Z, Huang C. Electroacupuncture ameliorates mechanical hypersensitivity by down-regulating spinal Janus kinase 2/signal transducer and activation of transcription 3 and interleukin 6 in rats with spared nerve injury. Acupunct Med 2021; 39:358-366. [PMID: 32744065 DOI: 10.1177/0964528420938376] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Evidence shows that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway participates in the pathogenesis of neuropathic pain. Our previous study revealed that electroacupuncture (EA) attenuated neuropathic pain via activation of alpha-7 nicotinic acetylcholine receptor (α7nAChR) in the spinal cord. However, whether 2 Hz EA alleviates neuropathic pain by regulating the downstream molecules JAK2/STAT3 has not been fully clarified. METHODS Paw withdrawal threshold (PWT) was used as a marker of mechanical allodynia in rats with spared nerve injury (SNI). After applying 2 Hz EA on day 3, 7, 14 and 21 post-surgery, spinal expression of JAK2, STAT3 and pro-inflammatory cytokine interleukin (IL)-6 was examined using quantitative reverse transcription and real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Intrathecal injection of the α7nAChR antagonist alpha-bungarotoxin (α-Bgtx) was used to further explore the mechanism underlying the effects of 2 Hz EA on expression of JAK2/STAT3 in SNI rats. RESULTS It was found that levels of spinal STAT3 and IL-6 mRNA, as well as levels of phosphorylated (p)-JAK2, p-STAT3 and IL-6 protein, were markedly increased in SNI rats. 2 Hz EA attenuated the SNI-induced up-regulation of p-JAK2, p-STAT3 and IL-6 expression in the spinal cord. Furthermore, intrathecal injection of α-Bgtx (1.0 μg/kg) not only inhibited the effect of 2 Hz EA on mechanical hypersensitivity but also ameliorated the down-regulation of p-JAK2, p-STAT3 and IL-6 expression induced by 2 Hz EA. CONCLUSION This study revealed that 2 Hz EA attenuated SNI-induced mechanical hypersensitivity and the concomitant up-regulation of spinal JAK2, STAT3 and IL-6 in SNI rats, suggesting that suppression of the JAK2/STAT3 signaling pathway might be the mechanism underlying the therapeutic effect of 2 Hz EA on neuropathic pain.
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Affiliation(s)
- Ying Wang
- Department of Physiology, Gannan Medical University, Ganzhou, P.R. China
| | - Yang-Yang Xia
- Department of Physiology, Gannan Medical University, Ganzhou, P.R. China
| | - Meng Xue
- Department of Physiology, Gannan Medical University, Ganzhou, P.R. China
| | - Qian Jiang
- Department of Physiology, Gannan Medical University, Ganzhou, P.R. China
| | - Zhihua Huang
- Department of Physiology, Gannan Medical University, Ganzhou, P.R. China
- Pain Medicine Research Institute, Gannan Medical University, Ganzhou, P.R. China
| | - Cheng Huang
- Department of Physiology, Gannan Medical University, Ganzhou, P.R. China
- Pain Medicine Research Institute, Gannan Medical University, Ganzhou, P.R. China
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16
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Fan B, Mohammed A, Huang Y, Luo H, Zhang H, Tao S, Xu W, Liu Q, He T, Jin H, Sun M, Sun M, Yun Z, Zhao R, Wu G, Li X. Can Aspirin Use Be Associated With the Risk or Prognosis of Bladder Cancer? A Case-Control Study and Meta-analytic Assessment. Front Oncol 2021; 11:633462. [PMID: 34350107 PMCID: PMC8327774 DOI: 10.3389/fonc.2021.633462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 06/30/2021] [Indexed: 12/03/2022] Open
Abstract
Aspirin, widely used to prevent cardiovascular disease, had been linked to the incidence of bladder cancer (BCa). Existing studies focusing on Chinese populations are relatively rare, especially for Northeast China. Meanwhile, relevant studies on the effects of aspirin on the occurrence or prognosis of BCa are inconsistent or even controversial. First, in the case control study, logistic regression analysis was used to investigate the association between aspirin intake and risk of BCa including 1121 patients with BCa and the 2242 controls. Subsequently, Kaplan-Meier curve and Cox regression analyses were applied to explore the association between aspirin intake and clinicopathological factors which may predict overall survival (OS) and recurrence-free survival (RFS) of BCa patients. Finally, we quantificationally combined the results with those from the published literature evaluating aspirin intake and its effects on the occurrence, outcome of surgery and prognosis of BCa by meta-analysis up to May 1, 2021.Our case-control study demonstrated that the regular use of aspirin was not associated with a reduced incidence of BCa (P=0.175). Stratified analyses of sex showed that aspirin intake did not lead to a lower risk of BCa in female patients (P=0.063). However, the male population who regularly took aspirin had a lower incidence of BCa (OR=0.748, 95% CI= 0.584-0.958, P=0.021). Subgroup analyses stratified by smoking found a significant reduction in the risk of BCa in current smokers with aspirin intake (OR=0.522, 95% CI=0.342-0.797, P=0.002). In terms of prognosis of BCa, patients with a history of aspirin intake did not had a markedly longer OS or RFS than those with no history of aspirin intake by Kaplan-Meier curves. Stratified analysis by sex showed no correlation between aspirin intake and the recurrence or survival of BCa for either male or female patients. However, in people younger than 68, aspirin intake seemed to have prolonged effects for overall survival (HR=3.876; 95% CI=1.326-11.325, P=0.019). Then, we performed a meta-analysis and the combined results from 19 articles and our study involving more than 39524 BCa cases indicated that aspirin intake was not associated with the occurrence of BCa (P=0.671). Subgroup analysis by whether regular use of aspirin, by the mean duration of use of aspirin, by sex, by smoking exposure, by research region and by study type also supported the above results. In terms of the impact of aspirin intake on the prognosis of patients with BCa, 11 articles and our study involving 8825 BCa cases were eligible. The combined results showed that patients with aspirin intake did not have significantly influence on survival, recurrence, progression and metastasis than those without aspirin intake. On the whole, both our retrospective study and literature meta-analysis suggested a lack of a strong relevant association between the use of aspirin and the incidence or prognosis of BCa. Thus, additional long-term follow-up prospective research is warranted to clarify the association of aspirin with BCa incidence and prognosis.
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Affiliation(s)
- Bo Fan
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Alradhi Mohammed
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuanbin Huang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hong Luo
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Hongxian Zhang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shenghua Tao
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Weijiao Xu
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Qian Liu
- Medical Imaging, Dalian Medical University, Dalian, China
| | - Tao He
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Huidan Jin
- Department of Anaesthesiology, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China
| | - Mengfan Sun
- Department of Pharmacy, Zhongshan College of Dalian Medical University, Dalian, China
| | - Man Sun
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Zhifei Yun
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Rui Zhao
- Department of Pharmacy, Zhongshan College of Dalian Medical University, Dalian, China
| | - Guoyu Wu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiancheng Li
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
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Bhat GR, Hyole RG, Li J. Head and neck cancer: Current challenges and future perspectives. Adv Cancer Res 2021; 152:67-102. [PMID: 34353444 DOI: 10.1016/bs.acr.2021.05.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Head and neck cancers are a heterogeneous, aggressive and genetically complex collection of malignancies of the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses and salivary glands, which are difficult to treat. About 90% of all head and neck cancers are squamous cell carcinomas (HNSCC). Larynx and Oral cavity carcinomas are generally related with tobacco consumption, alcohol abuse (or both), but pharynx carcinomas are generally associated with infection of human papillomavirus (HPV), especially HPV-16 subtype. Thus, usually HNSCC can be separated into HPV-negative and HPV-positive categories. Despite substantial efforts invested into therapeutic development of HNSCC, the 5-year survival rate of patients with HNSCC still remains dismal. The primary reason being late diagnosis, recurrent metastasis, relapse and resistance to therapies. Currently surgery and radiotherapy represent the baseline treatment options for most initial stage HNSCC patients, but these treatments are associated with significant morbidity and poor prognosis. Moreover, the issue of resistance to both radiotherapy/chemotherapy and recurrent relapse are common in HNSCC. Elucidation of the genetic landscape, tumor microenvironment and aberrant signaling pathways have generated new insights into the molecular pathogenesis of this disease. Thus, the scientific research has therefore been focused on the understanding of HNSCC biology and immunobiology to identification of predictive/prognostic biomarkers, which will be key to develop more effective targeted therapies with less toxicity and high specificity.
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Affiliation(s)
- Gh Rasool Bhat
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States
| | - Rosalie G Hyole
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States
| | - Jiong Li
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States; Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Virginia Commonwealth University, Richmond, VA, United States; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, VA, United States.
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Han QQ, Deng MY, Liu H, Ali U, Li XY, Wang YX. Cynandione A and PHA-543613 inhibit inflammation and stimulate macrophageal IL-10 expression following α7 nAChR activation. Biochem Pharmacol 2021; 190:114600. [PMID: 33992630 DOI: 10.1016/j.bcp.2021.114600] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 10/21/2022]
Abstract
Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, attenuates inflammation. The present study aimed to study the mechanisms underlying cynandione A-induced antiinflammation. Treatment with cynandione A and the specific α7 nicotinic acetylcholine receptor (α7 nAChR) agonist PHA-543613 remarkably reduced overexpression of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells and primary peritoneal macrophages, and endotoxemic mice. Both cynandione A and PHA-543613 also stimulated IL-10 expression in naïve and LPS-treated macrophages and endotoxemic mice. Cynandione A- and PHA-543613-inhibited proinflammatory cytokine expression was completely blocked by the α7 nAChR antagonist methyllycaconitine and the IL-10 antibody. The stimulatory effect of cynandione A and PHA-543613 on IL-10 expression were suppressed by methyllycaconitine and knockdown of α7 nAChRs using siRNA/α7 nAChR. Cynandione A significantly stimulated STAT3 phosphorylation, which was attenuated by methyllycaconitine and the IL-10 neutralizing antibody. The STAT3 activation inhibitor NSC74859 also blocked cynandione A-inhibited proinflammatory cytokine expression. Taken together, our results, for the first time, demonstrate that cynandione A and PHA-543613 inhibit inflammation through macrophageal α7 nAChR activation and subsequent IL-10 expression.
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Affiliation(s)
- Qiao-Qiao Han
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China
| | - Meng-Yan Deng
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China
| | - Hao Liu
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China
| | - Usman Ali
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China
| | - Xin-Yan Li
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China
| | - Yong-Xiang Wang
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China.
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Kobayashi K, Hirono Y, Nakta H, Pinkerton KE, Takeuchi M. Cigarette Smoke Exposure Inhibits Early Phase of Antibody Production through Inhibition of Immune Functions in Alveolar Macrophage. CURRENT RESPIRATORY MEDICINE REVIEWS 2021. [DOI: 10.2174/1573398x16999201105162114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background::
Cigarette smoke (CS) is inhaled into the lung. Alveolar macrophage (AM)
is known to play an important role in the lung immune system. However, the relationship between
AM functions and antibody production by CS is not fully investigated.
Objective::
Therefore, we investigated the effects of AM from CS exposed mice on antibody production.
Mice were exposed to 20 cigarettes/day for 10 days. AM were obtained by broncho-alveolar
lavage. Antibody production was analyzed by plaque-forming cell assay using seep red blood
cell (SRBC) as antigen.
Methods::
B cell proliferation was analyzed by 3H-thymidine incorporation. Phagocytic activity using
fluorescein isothiocyanate-labeled SRBC and expressions of surface antigens on AM were analyzed
by flow cytometry. Cytokines and NF-κB mRNA expressions of AM were analyzed by RTPCR.
Results and Discussion:
Antibody production was decreased at the induction phase, but not at the
expression phase by AM from smoked mice (SM) compared with non-smoked mice (NSM). B cell
proliferation was decreased by cigarette extracts dose-dependently. Phagocytic activity of AM was
decreased in SM compared with NSM. Expression of surface antigens on AM was decreased in
SM compared with NSM. Cytokines or NF-κB mRNA expressions of AM were decreased in SM
compared with NSM.
Conclusion::
These results suggest that the inhibition of antibody production by cigarette smoking
is caused by the inhibition of phagocytosis and expressions of surface antigens associated with antigen
presentation. Such inhibition of AM functions may increase the risk of bacterial and virus infections.
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Affiliation(s)
- Kengo Kobayashi
- Department of Animal Medical Science, Kyoto Sangyo University, Kyoto, Japan
| | - Yuriko Hirono
- Department of Animal Medical Science, Kyoto Sangyo University, Kyoto, Japan
| | - Honami Nakta
- Department of Animal Medical Science, Kyoto Sangyo University, Kyoto, Japan
| | - Kent E. Pinkerton
- Center for Health and the Environment, University of California Davis, Davis, CA, United States
| | - Minoru Takeuchi
- Department of Animal Medical Science, Kyoto Sangyo University, Kyoto, Japan
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20
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Nicotinic Acetylcholine Receptor Involvement in Inflammatory Bowel Disease and Interactions with Gut Microbiota. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18031189. [PMID: 33572734 PMCID: PMC7908252 DOI: 10.3390/ijerph18031189] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022]
Abstract
The gut-brain axis describes a complex interplay between the central nervous system and organs of the gastrointestinal tract. Sensory neurons of dorsal root and nodose ganglia, neurons of the autonomic nervous system, and immune cells collect and relay information about the status of the gut to the brain. A critical component in this bi-directional communication system is the vagus nerve which is essential for coordinating the immune system’s response to the activities of commensal bacteria in the gut and to pathogenic strains and their toxins. Local control of gut function is provided by networks of neurons in the enteric nervous system also called the ‘gut-brain’. One element common to all of these gut-brain systems is the expression of nicotinic acetylcholine receptors. These ligand-gated ion channels serve myriad roles in the gut-brain axis including mediating fast synaptic transmission between autonomic pre- and postganglionic neurons, modulation of neurotransmitter release from peripheral sensory and enteric neurons, and modulation of cytokine release from immune cells. Here we review the role of nicotinic receptors in the gut-brain axis with a focus on the interplay of these receptors with the gut microbiome and their involvement in dysregulation of gut function and inflammatory bowel diseases.
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21
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Han QQ, Yin M, Wang ZY, Liu H, Ao JP, Wang YX. Cynandione A Alleviates Neuropathic Pain Through α7-nAChR-Dependent IL-10/β-Endorphin Signaling Complexes. Front Pharmacol 2021; 11:614450. [PMID: 33584292 PMCID: PMC7873367 DOI: 10.3389/fphar.2020.614450] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022] Open
Abstract
Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antineuropathic pain effect. This study further explored the target molecule and signaling mechanisms underlying cynandione-A-induced antineuropathic pain. Intrathecal injection of cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased spinal expression of IL-10 and β-endorphin but not dynorphin A. Cynandione A treatment also enhanced expression of IL-10 and β-endorphin but not α7 nicotinic acetylcholine receptors (nAChRs) in cultured microglia. The IL-10 antibody attenuated cynandione-A-induced spinal or microglial gene expression of β-endorphin and mechanical allodynia, whereas the β-endorphin antiserum blocked cynandione-A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly reduced cynandione-A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Furthermore, cynandione A stimulated microglial phosphorylation of PKA, p38, and CREB in an α7-nAChR-dependent manner, and treatment with their inhibitors attenuated cynandione-A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. In addition, cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, the PKA activation inhibitor or IL-10 antibody. The STAT3 inhibitor NSC74859 also abolished cynandione-A-induced mechanical antiallodynia and spinal expression of β-endorphin. These findings suggest that cynandione A suppresses neuropathic pain through α7-nAChR-dependent IL-10/β-endorphin signaling pathway in spinal microglia.
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Affiliation(s)
- Qiao-Qiao Han
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China
| | - Min Yin
- Jiangsu Key Laboratory for the Research and Utilization of Plants Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing, China
| | - Zi-Ying Wang
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China
| | - Hao Liu
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China
| | - Jun-Ping Ao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yong-Xiang Wang
- King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China
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22
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Kakinuma Y. Characteristic Effects of the Cardiac Non-Neuronal Acetylcholine System Augmentation on Brain Functions. Int J Mol Sci 2021; 22:ijms22020545. [PMID: 33430415 PMCID: PMC7826949 DOI: 10.3390/ijms22020545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 02/07/2023] Open
Abstract
Since the discovery of non-neuronal acetylcholine in the heart, this specific system has drawn scientific interest from many research fields, including cardiology, immunology, and pharmacology. This system, acquired by cardiomyocytes independent of the parasympathetic nervous system of the autonomic nervous system, helps us to understand unsolved issues in cardiac physiology and to realize that the system may be more pivotal for cardiac homeostasis than expected. However, it has been shown that the effects of this system may not be restricted to the heart, but rather extended to cover extra-cardiac organs. To this end, this system intriguingly influences brain function, specifically potentiating blood brain barrier function. Although the results reported appear to be unusual, this novel characteristic can provide us with another research interest and therapeutic application mode for central nervous system diseases. In this review, we discuss our recent studies and raise the possibility of application of this system as an adjunctive therapeutic modality.
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Affiliation(s)
- Yoshihiko Kakinuma
- Department of Bioregulatory Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan
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23
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Wu YJ, Wang L, Ji CF, Gu SF, Yin Q, Zuo J. The Role of α7nAChR-Mediated Cholinergic Anti-inflammatory Pathway in Immune Cells. Inflammation 2021; 44:821-834. [PMID: 33405021 DOI: 10.1007/s10753-020-01396-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/05/2020] [Accepted: 12/07/2020] [Indexed: 12/14/2022]
Abstract
Alpha 7 nicotinic acetylcholine receptor (α7nAChR) is widely distributed in the nervous and non-cholinergic immune systems. It is necessary for the cholinergic transmitter to participate in the regulation of inflammatory response and is the key element of cholinergic anti-inflammatory pathway (CAP). Because of the profound impact of CAP on the immune system, α7nAChR is considered as a potential therapeutic target for the treatment of inflammatory diseases. Available evidences confirmed that manipulation of CAP by activating α7nAChR with either endogenous acetylcholine (ACh) or cholinergic agonists can substantially alleviate inflammatory responses both in vivo and in vitro. However, the mechanism through which CAP curbs the excessive pro-inflammatory responses and maintains immune homeostasis is not fully understood. Obtained clues suggest that the crosstalk between CAP and classical inflammatory pathways is the key to elucidate the anti-inflammatory mechanism, and the impacts of CAP activation in α7nAChR-expressing immune cells are the foundation of the immunoregulatory property. In this article, we review and update the knowledge concerning the progresses of α7nAChR-based CAP, including α7nAChR properties, signal transductions, interactions with classic immune pathways, and immunoregulatory functions in different immune cells. Certain critical issues to be addressed are also highlighted. By providing a panoramic view of α7nAChR, the summarized evidences will pave the way for the development of novel anti-inflammatory reagents and strategy and inspire further researches.
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Affiliation(s)
- Yi-Jin Wu
- The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
| | - Li Wang
- Department of Pharmacy, Wuhu Medicine and Health School, Wuhu, 241000, China
| | - Chao-Fan Ji
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Shao-Fei Gu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Qin Yin
- The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China.
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China.
| | - Jian Zuo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China.
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, China.
- Research Center of Integrated Traditional and Western Medicine, Wannan Medical College, 241000, Wuhu, China.
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24
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Jimenez T, Friedman T, Vadgama J, Singh V, Tucker A, Collazo J, Sinha S, Hikim AS, Singh R, Pervin S. Nicotine Synergizes with High-Fat Diet to Induce an Anti-Inflammatory Microenvironment to Promote Breast Tumor Growth. Mediators Inflamm 2020; 2020:5239419. [PMID: 33414685 PMCID: PMC7752272 DOI: 10.1155/2020/5239419] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/26/2020] [Accepted: 11/25/2020] [Indexed: 01/03/2023] Open
Abstract
Breast cancer results from a complex interplay of genetics and environment that alters immune and inflammatory systems to promote tumorigenesis. Obesity and cigarette smoking are well-known risk factors associated breast cancer development. Nicotine known to decrease inflammatory signals also modulates immune responses that favor breast cancer development. However, the mechanisms by which nicotine and obesity contribute to breast cancer remain poorly understood. In this study, we examined potential mechanisms by which nicotine (NIC) and high-fat diet (HFD) promote growth of HCC70 and HCC1806 xenografts from African American (AA) triple negative (TN) breast cancer cells. Immunodeficient mice fed on HFD and treated with NIC generated larger HCC70 and HCC1806 tumors when compared to NIC or HFD alone. Increased xenograft growth in the presence of NIC and HFD was accompanied by higher levels of tissue-resident macrophage markers and anti-inflammatory cytokines including IL4, IL13, and IL10. We further validated the involvement of these players by in vitro and ex vivo experiments. We found a proinflammatory milieu with increased expression of IL6 and IL12 in xenografts with HFD. In addition, nicotine or nicotine plus HFD increased a subset of mammary cancer stem cells (MCSCs) and key adipose browning markers CD137 and TMEM26. Interestingly, there was upregulation of stress-induced pp38 MAPK and pERK1/2 in xenografts exposed to HFD alone or nicotine plus HFD. Scratch-wound assay showed marked reduction in proliferation/migration of nicotine and palmitate-treated breast cancer cells with mecamylamine (MEC), a nicotine acetylcholine receptor (nAchR) antagonist. Furthermore, xenograft development in immune-deficient mice, fed HFD plus nicotine, was reduced upon cotreatment with MEC and SB 203580, a pp38MAPK inhibitor. Our study demonstrates the presence of nicotine and HFD in facilitating an anti-inflammatory tumor microenvironment that influences breast tumor growth. This study also shows potential efficacy of combination therapy in obese breast cancer patients who smoke.
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Affiliation(s)
- Thalia Jimenez
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Theodore Friedman
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Jaydutt Vadgama
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Division of Cancer Research and Training, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Vineeta Singh
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Alexandria Tucker
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Javier Collazo
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Satyesh Sinha
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Amiya Sinha Hikim
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Rajan Singh
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Shehla Pervin
- Division of Endocrinology and Metabolism, Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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25
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Stegemann A, Böhm M. Targeting the α7 nicotinic acetylcholine receptor-A novel road towards the future treatment of skin diseases. Exp Dermatol 2020; 29:924-931. [PMID: 32780438 DOI: 10.1111/exd.14173] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022]
Abstract
Nicotinic acetylcholine receptors (nAChRs) are members of the superfamily of neurotransmitter-gated ion channels. The natural ligand for nAChRs is the endogenous neurotransmitter acetylcholine. Among the nAChRs is the α7nAChR. It is not only expressed by neural tissues but also in the skin. A number of different resident cutaneous cell types including epidermal keratinocytes, sebocytes and dermal fibroblasts express functional α7nAChR. Moreover, cells of the immune system such as lymphocytes, macrophages and monocytes, playing an important role in skin homeostasis, also express α7nAChR. Translational research focusing on the exploitation of the α7nAChR in dermatology has revealed that this neuroendocrine receptor could be promising target for the treatment of inflammatory skin diseases. For example, α7nAChR agonists can counteract transforming growth factor-β1-mediated responses in dermal fibroblasts, key effector cells in scleroderma. In accordance with this α7nAChR, agonists are effective in both inflammation and non-inflammation-driven models of experimentally induced skin fibrosis. Moreover, α7nAChR agonists can modulate expression of proinflammatory cytokines in epidermal keratinocytes that are crucially involved in the pathogenesis of psoriasis and other inflammatory skin diseases. Finally, the capability of α7nAChR agonists to suppress ultraviolet light A/B-induced responses, for example production of proinflammatory cytokines and oxidative stress, the latter crucially involved in dermal photoageing, points to a potential of such agents in the prevention of extrinsic skin ageing. Therefore, emphasis on translational research targeting the α7nAChR in skin may lead to the development of new treatment and prevention modalities against fibrosclerotic skin diseases, psoriasis vulgaris, atopic dermatitis, acne, photodermatoses and extrinsic skin ageing.
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Affiliation(s)
| | - Markus Böhm
- Dept. of Dermatology, University of Münster, Germany
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26
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Stegemann A, Flis D, Ziolkowski W, Distler JHW, Steinbrink K, Böhm M. The α7 Nicotinic Acetylcholine Receptor: A Promising Target for the Treatment of Fibrotic Skin Disorders. J Invest Dermatol 2020; 140:2371-2379. [PMID: 32335129 DOI: 10.1016/j.jid.2020.04.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/19/2020] [Accepted: 04/03/2020] [Indexed: 12/20/2022]
Abstract
Targeting neuroendocrine receptors can be considered as another interesting approach to treating fibrotic disorders. Previously, we could demonstrate that tropisetron, a classical serotonin receptor blocker, can modulate collagen synthesis and acts in vitro through the α7 nicotinic acetylcholine receptor (α7nAchR). Here, we used a pharmacologic approach with specific α7nAchR agonists to validate this hypothesis. PHA-543613, an α7nAchR-specific agonist, not only prevented but also reversed established skin fibrosis of mice injected with bleomycin. Interestingly, agonistic stimulation of α7nAchR also attenuated experimental skin fibrosis in the non-inflammation driven adenovirus coding for TGFβ receptor Iact mouse model, indicating fibroblast-mediated and not only anti-inflammatory effects of such agents. The fibroblast-mediated effects were confirmed in vitro using human dermal fibroblasts, in which the α7nAchR-specific agonists strongly reduced the impact of TGFβ1-mediated expression on collagen and myofibroblast marker expression. These actions were linked to modulation of the redox-sensitive transcription factor JunB and impairment of the mitochondrial respiratory system. Our results indicate that pharmacologic stimulation of the α7nAchR could be a promising target for treatment of patients with skin fibrotic diseases. Moreover, our results suggest a mechanistic axis of collagen synthesis regulation through the mitochondrial respiratory system.
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Affiliation(s)
- Agatha Stegemann
- Department of Dermatology, University of Münster, Münster, Germany.
| | - Damian Flis
- Department of Bioenergetics and Nutrition, Gdańsk University of Physical Education and Sport, Gdańsk, Poland
| | - Wieslaw Ziolkowski
- Department of Rehabilitation Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Jörg H W Distler
- Institute for Rheumatology and Immunology, University of Erlangen, Erlangen, Germany
| | | | - Markus Böhm
- Department of Dermatology, University of Münster, Münster, Germany
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27
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Grando SA, Kawashima K, Wessler I. A historic perspective on the current progress in elucidation of the biologic significance of non-neuronal acetylcholine. Int Immunopharmacol 2020; 81:106289. [PMID: 32113128 PMCID: PMC10612399 DOI: 10.1016/j.intimp.2020.106289] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 02/03/2020] [Indexed: 01/05/2023]
Abstract
The "5th International Symposium on Non-neuronal Acetylcholine: from bench to bedside" was held on September 27-29, 2019 in Hyatt Regency, Long Beach, CA, USA. Approximately 50 scientists from 11 countries over 6 continents participated in this meeting. The major topics included an overall biologic significance of non-neuronal acetylcholine (ACh) and the roles of the non-neuronal cholinergic systems in mucocutaneous, respiratory, digestive, immunologic, endocrine, cardiovascular, musculoskeletal and kidney diseases, and cancer. This meeting facilitated continued work to advance the fundamental science and translational aspects of the interdisciplinary studies on non-neuronal ACh. The progress made has opened a new chapter in the field of cholinergic pharmacology, and advanced our knowledge beyond regulation of individual cell- and tissue-types, defining a new paradigm of selective pharmacological regulation of vital function of practically all types of non-neuronal cells. It is now clear that the autocrine and paracrine control of non-neuronal cells by non-neuronal ACh is implemented through synergistic, additive, and reciprocal effects triggered by two different cholinergic receptor classes. Each biologic effect of ACh is determined by a unique combination of cholinergic receptors subtype expressed at each stage of cell development and differentiation. The plasticity of the non-neuronal cholinergic system helps adjust homeostasis to new environmental conditions.
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Affiliation(s)
- Sergei A Grando
- Department of Dermatology, University of California, Irvine, CA 92697, USA
| | - Koichiro Kawashima
- Department of Molecular Pharmacology, Kitasato University School of Pharmacy, Tokyo 108-8641, Japan
| | - Ignaz Wessler
- Institute of Pathology, University Medical Center, Johannes Gutenberg-University, Mainz D-55101, Germany
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28
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Arshad S, Naveed M, Ullia M, Javed K, Butt A, Khawar M, Amjad F. Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges. Genet Mol Biol 2020; 43:e20180160. [PMID: 32167126 PMCID: PMC7198026 DOI: 10.1590/1678-4685-gmb-2018-0160] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 10/20/2018] [Indexed: 12/25/2022] Open
Abstract
Signal transducers and activators of transcription 3 (STAT-3) is a transcription
factor that regulates the gene expression of several target genes. These factors
are activated by the binding of cytokines and growth factors with STAT-3
specific receptors on cell membrane. Few years ago, STAT-3 was considered an
acute phase response element having several cellular functions such as
inflammation, cell survival, invasion, metastasis and proliferation, genetic
alteration, and angiogenesis. STAT-3 is activated by several types of
inflammatory cytokines, carcinogens, viruses, growth factors, and oncogenes.
Thus, the STAT3 pathway is a potential target for cancer therapeutics. Abnormal
STAT-3 activity in tumor development and cellular transformation can be targeted
by several genomic and pharmacological methodologies. An extensive review of the
literature has been conducted to emphasize the role of STAT-3 as a unique cancer
drug target. This review article discusses in detail the wide range of STAT-3
inhibitors that show antitumor effects both in vitro and
in vivo. Thus, targeting constitutive STAT-3 signaling is a
remarkable therapeutic methodology for tumor progression. Finally, current
limitations, trials and future perspectives of STAT-3 inhibitors are also
critically discussed.
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Affiliation(s)
- Sundas Arshad
- University of Lahore, Department of Allied Health Sciences, Gujrat Campus, Pakistan
| | - Muhammad Naveed
- University of Central Punjab, Faculty of life sciences, Department of Biotechnology, Lahore, Pakistan
| | - Mahad Ullia
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Khadija Javed
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Ayesha Butt
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Masooma Khawar
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
| | - Fazeeha Amjad
- University of Gujrat, Department of Biochemistry and Biotechnology Sialkot sub Campus, Pakistan
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29
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Chen X, Jia Y, Zhang Y, Zhou D, Sun H, Ma X. α5-nAChR contributes to epithelial-mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer. J Cell Mol Med 2020; 24:2497-2506. [PMID: 31930655 PMCID: PMC7028847 DOI: 10.1111/jcmm.14941] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 10/31/2019] [Accepted: 11/26/2019] [Indexed: 12/14/2022] Open
Abstract
Recent studies have showed that α5 nicotinic acetylcholine receptor (α5‐nAChR) is closely associated with nicotine‐related lung cancer. Our previous studies also demonstrated that α5‐nAChR mediates nicotine‐induced lung carcinogenesis. However, the mechanism by which α5‐nAChR functions in lung carcinogenesis remains to be elucidated. Jab1/Csn5 is a key regulatory factor in smoking‐induced lung cancer. In this study, we explored the underlying mechanisms linking the α5‐nAChR‐Jab1/Csn5 axis with lung cancer epithelial‐mesenchymal transition (EMT) and metastasis, which may provide potential therapeutic targets for future lung cancer treatments. Our results demonstrated that the expression of α5‐nAChR was correlated with the expression of Jab1/Csn5 in lung cancer tissues and lung cancer cells. α5‐nAChR expression is associated with Jab1/Csn5 expression in lung tumour xenografts in mice. In vitro, the expression of α5‐nAChR mediated Stat3 and Jab1/Csn5 expression, significantly regulating the expression of the EMT markers, N‐cadherin and Vimentin. In addition, the down‐regulation of α5‐nAChR or/and Stat3 reduced Jab1/Csn5 expression, while the silencing of α5‐nAChR or Jab1/Csn5 inhibited the migration and invasion of NSCLC cells. Mechanistically, α5‐nAChR contributes to EMT and metastasis by regulating Stat3‐Jab1/Csn5 signalling in NSCLC, suggesting that α5‐nAChR may be a potential target in NSCLC diagnosis and immunotherapy.
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Affiliation(s)
- Xiaowei Chen
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Yanfei Jia
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | | | - Dajie Zhou
- Weifang Medical University, Weifang, China
| | - Haiji Sun
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, Jinan, China
| | - Xiaoli Ma
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
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30
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Blaylock RL. Accelerated cancer aggressiveness by viral oncomodulation: New targets and newer natural treatments for cancer control and treatment. Surg Neurol Int 2019; 10:199. [PMID: 31768279 PMCID: PMC6826277 DOI: 10.25259/sni_361_2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 06/19/2019] [Indexed: 12/12/2022] Open
Abstract
An infectious etiology for a number of cancers has been entertained for over 100 years and modern studies have confirmed that a number of viruses are linked to cancer induction. While a large number of viruses have been demonstrated in a number of types of cancers, most such findings have been dismissed in the past as opportunistic infections, especially with persistent viruses with high rates of infectivity of the world’s populations. More recent studies have clearly shown that while not definitely causing these cancers, these viruses appear capable of affecting the biology of these tumors in such a way as to make them more aggressive and more resistant to conventional treatments. The term oncomodulatory viruses has been used to describe this phenomenon. A number of recent studies have shown a growing number of ways these oncomodulatory viruses can alter the pathology of these tumors by affecting cell-signaling, cell metabolism, apoptosis mechanisms, cell-cell communication, inflammation, antitumor immunity suppression, and angiogenesis. We are also learning that much of the behavior of tumors depends on cancer stem cells and stromal cells within the tumor microenvironment, which participate in extensive, dynamic crosstalk known to affect tumor behavior. Cancer stem cells have been found to be particularly susceptible to infection by human cytomegalovirus. In a number of studies, it has been shown that while only a select number of cells are actually infected with the virus, numerous viral proteins are released into cancer and stromal cells in the microenvironment and these viral proteins are known to affect tumor behavior and aggressiveness.
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Han R, Zhang G, Qiao X, Guo Y, Sun L, Li J, Gao C, Sun X. α7 Nicotinic Acetylcholine Receptor Mediates the Neuroprotection of Remote Ischemic Postconditioning in a Rat Model of Asphyxial Cardiac Arrest. J Surg Res 2019; 246:6-18. [PMID: 31541709 DOI: 10.1016/j.jss.2019.07.091] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/10/2019] [Accepted: 07/23/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Remote ischemic postconditioning (RIPost) has been shown to reduce the ischemia-reperfusion injury of the heart and brain. However, the protection mechanisms have not yet been fully elucidated. We have observed that RIPost could alleviate the brain injury after cardiac arrest (CA). The aim of this study was to explore whether α7 nicotinic acetylcholine receptor (α7nAChR) mediates the neuroprotection of RIPost in a rat model of asphyxial CA. MATERIALS AND METHODS Asphyxial CA model was induced by occlusion of the tracheal tube for 8 min and resuscitated later. RIPost produced by three cycles of 15-min occlusion and 15-min release of the right hind limb by a tourniquet was performed respectively at the moment and the third hour after restoration of spontaneous circulation. The α7nAChR agonist PHA-543613 and the antagonist methyllycaconitine (MLA) were used to investigate the role of α7nAChR in mediating neuroprotective effects. RESULTS Results showed that α7nAChR was decreased in hippocampus and cortex after resuscitation, whereas RIPost could attenuate the reduction. The use of PHA-543613 provided neuroprotective effects against cerebral injury after CA. Furthermore, RIPost decreased the levels of neuron-specific enolase, inflammatory mediators, the number of apoptotic cells, and phosphorylation of nuclear factor-κB while increased the phosphorylation of signal transducer and activator of transcription-3. However, the above effects of RIPost were attenuated by α7nAChR antagonist methyllycaconitine. CONCLUSIONS Neuroprotection of RIPost was related with the activation of α7nAChR, which could suppress nuclear factor-κB and activate signal transducer and activator of transcription-3 in a rat asphyxial CA model.
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Affiliation(s)
- Ruili Han
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Tangdu Hospital of Fourth Military Medical University, Xi'an, China
| | - Guihe Zhang
- Department of Anesthesiology, Daxing Hospital, Xi'an, China
| | - Xiaoli Qiao
- Department of Anesthesiology, The Fourth People's Hospital of Shaanxi Province, Xi'an, China
| | - Yu Guo
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Tangdu Hospital of Fourth Military Medical University, Xi'an, China
| | - Li Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Tangdu Hospital of Fourth Military Medical University, Xi'an, China
| | - Jiangjing Li
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Tangdu Hospital of Fourth Military Medical University, Xi'an, China
| | - Changjun Gao
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Tangdu Hospital of Fourth Military Medical University, Xi'an, China.
| | - Xude Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Tangdu Hospital of Fourth Military Medical University, Xi'an, China.
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Wang Y, Xue M, Xia Y, Jiang Q, Huang Z, Huang C. Electroacupuncture treatment upregulates α7nAChR and inhibits JAK2/STAT3 in dorsal root ganglion of rat with spared nerve injury. J Pain Res 2019; 12:1947-1955. [PMID: 31308727 PMCID: PMC6613452 DOI: 10.2147/jpr.s203867] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/27/2019] [Indexed: 12/23/2022] Open
Abstract
Background Neuropathic pain with complicated mechanism severely disrupts patient quality of life. The novel approaches and more effective management should be further investigated. It was reported that alpha-7 nicotinic acetylcholine receptor (α7nAChR) and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in dorsal root ganglion (DRG) contributed to the pathogenesis of neuropathic pain. Our previous study has shown that electroacupuncture (EA) alleviated neuropathic pain via activating α7nAChR in the spinal cord. However, whether the effect of 2 Hz EA on spared nerve injury (SNI)-induced neuropathic pain is mediated through modulation of α7nAChR and JAK2/STAT3 pathway in the DRG remains unclear. Materials and methods The SNI-induced neuropathic pain rat model was used in this study. After application of 2 Hz EA treatment to SNI rats on day 3, 7, 14 and 21 post-surgery, the expression levels of α7nAChR, JAK2/STAT3 and some cytokines in DRG were determined by qRT-PCR and Western blot analysis. Results We found that SNI induced significant down-regulation of α7nAChR mRNA and protein expression. SNI also obviously elicited the decrease in anti-inflammatory cytokine IL-10 protein expression. The enhancement of p-JAK2, p-STAT3, pro-inflammatory cytokines IL-1β and IL-6 protein levels induced by SNI were also observed. However, 2 Hz EA treatment to SNI rats distinctly improved α7nAChR and IL-10 levels and reduced p-JAK2, p-STAT3, IL-1β and IL-6 expression in the DRG. Conclusion Our present study suggested that 2 Hz EA treatment indeed activated α7nAChR, suppressed JAK2/STAT3 signaling and re-balanced the relationship between pro-inflammatory and anti-inflammatory cytokines in DRG of SNI rat, which provided insight into our understanding of the mechanism for 2 Hz EA to attenuate neuropathic pain.
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Affiliation(s)
- Ying Wang
- Department of Physiology, Gannan Medical University, Ganzhou 341000, People's Republic of China
| | - Meng Xue
- Department of Physiology, Gannan Medical University, Ganzhou 341000, People's Republic of China
| | - Yangyang Xia
- Department of Physiology, Gannan Medical University, Ganzhou 341000, People's Republic of China
| | - Qian Jiang
- Department of Physiology, Gannan Medical University, Ganzhou 341000, People's Republic of China
| | - Zhihua Huang
- Department of Physiology, Gannan Medical University, Ganzhou 341000, People's Republic of China.,Pain Medicine Research Institute, Gannan Medical University, Ganzhou 341000, People's Republic of China
| | - Cheng Huang
- Department of Physiology, Gannan Medical University, Ganzhou 341000, People's Republic of China.,Pain Medicine Research Institute, Gannan Medical University, Ganzhou 341000, People's Republic of China
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Zhao Z, Liu B, Sun J, Lu L, Liu L, Qiu J, Li Q, Yan C, Jiang S, Mohammadtursun N, Ma W, Li M, Dong J, Gong W. Scutellaria Flavonoids Effectively Inhibit the Malignant Phenotypes of Non-small Cell Lung Cancer in an Id1-dependent Manner. Int J Biol Sci 2019; 15:1500-1513. [PMID: 31337979 PMCID: PMC6643150 DOI: 10.7150/ijbs.33146] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 04/23/2019] [Indexed: 12/17/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the world. Inhibitor of differentiation 1 (Id1) is overexpressed in NSCLC and involved in promoting its progression and metastasis. Identifying natural compounds targeting Id1 may have utility in NSCLC treatment. Here, we sought to determine whether the anti-tumor activities of Scutellaria flavonoids (SFs) were related to Id1. We reported that three SFs (baicalin, baicalein and wogonin) exhibited strong antitumor activity in NSCLC cells in vitro and in vivo. Id1 played a pivotal role on blockage of migration and invasion by SFs. Abrogation of invasion and migration mediated by baicalin, baicalein and wogonin were totally abolished by ectopic overexpression of Id1. Mechanistically, baicalin, baicalein and wogonin activated Rap1-GTP binding and dephosphorylated Akt and Src by suppressing a7nAChR, consequently triggering inhibition of Id1. Then attenuation of its downstream mediators, VEGF-A, N-cadherin, vimentin, combined with augment of E-cadherin led to the blockage of proliferation, EMT and angiogenesis of NSCLC. Overall, our data shed light on heretofore-undescribed role of SFs as modulators of Id1, which may be a useful strategy in the treatment of NSCLC.
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Affiliation(s)
- Zhengxiao Zhao
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Baojun Liu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Jing Sun
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Linwei Lu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Lumei Liu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Jian Qiu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Qiuping Li
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Chen Yan
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Shan Jiang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Nabijan Mohammadtursun
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Wenjuan Ma
- Department of dermatology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Mihui Li
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China.,Institutes of Integrative Medicine, Fudan University, Shanghai, PR China
| | - Jingcheng Dong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Weiyi Gong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, PR China
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Bono F, Mutti V, Savoia P, Barbon A, Bellucci A, Missale C, Fiorentini C. Nicotine prevents alpha-synuclein accumulation in mouse and human iPSC-derived dopaminergic neurons through activation of the dopamine D3- acetylcholine nicotinic receptor heteromer. Neurobiol Dis 2019; 129:1-12. [PMID: 31051233 DOI: 10.1016/j.nbd.2019.04.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 04/05/2019] [Accepted: 04/29/2019] [Indexed: 12/25/2022] Open
Abstract
We recently found that in mouse dopaminergic neurons, the heteromer formed by the dopamine D3 receptor (D3R) and the β2 subunit of acetylcholine nicotinic receptor (nAChR) exerts neurotrophic effects when activated by nicotine, leading to neurons with enlarged cell bodies and increased dendrite arborization. Beside this action, we now show that nicotine, by activating the D3R-nAChR heteromer, protects dopaminergic neurons against neuronal injury. In primary cultures of mouse dopaminergic neurons, in fact, the ability of nicotine to inhibit both the pathological accumulation of alpha-synuclein induced by glucose deprivation and the consequent morphological defects were strongly prevented by disrupting the D3R-nAChR heteromer with specific interfering TAT-peptides; the relevance of the phosphoinositide 3-kinase (PI3K) intracellular signaling in mediating nicotine prevention of alpha-synuclein aggregation has been also demonstrated. Moreover, the ability of nicotine in restoring the ubiquitin-proteasome system has been found as a mechanism contributing to the neuroprotective properties of nicotine. By using the proximity ligation assay, we have shown that the D3R-nAChR heteromer is also expressed in human dopaminergic neurons derived from induced pluripotent stem cells. In this human cell model, nicotine exerts neuroprotective effects specifically acting through the D3R-nAChR complex thus indicating that this heteromer is a relevant molecular effector involved in the protection of human dopaminergic neurons.
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Affiliation(s)
- Federica Bono
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; Laboratory of Personalized and Preventive Medicine, University of Brescia, 25123 Brescia, Italy
| | - Veronica Mutti
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Paola Savoia
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Alessandro Barbon
- Unit of Biology and Genetic, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Arianna Bellucci
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; Laboratory of Personalized and Preventive Medicine, University of Brescia, 25123 Brescia, Italy
| | - Cristina Missale
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Chiara Fiorentini
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
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Chen CJ, Ding D, Ironside N, Buell TJ, Southerland AM, Koch S, Flaherty M, Woo D, Worrall BB. Cigarette Smoking History and Functional Outcomes After Spontaneous Intracerebral Hemorrhage. Stroke 2019; 50:588-594. [PMID: 30732556 PMCID: PMC6389405 DOI: 10.1161/strokeaha.118.023580] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/02/2018] [Indexed: 12/24/2022]
Abstract
Background and Purpose- Although cigarette use may be a risk for intracerebral hemorrhage (ICH), animal models suggest that nicotine has a potential neuroprotective effect. The aim of this multicenter study is to determine the effect of smoking history on outcome in ICH patients. Methods- We analyzed prospectively collected data from the Ethnic/Racial Variations of Intracerebral Hemorrhage study and included patients with smoking status data in the analysis. Patients were dichotomized into nonsmokers versus ever-smokers, and the latter group was further categorized as former (>30 days before ICH) or current (≤30 days before ICH) smokers. The primary outcome was 90-day modified Rankin Scale score shift analysis. Secondary outcomes were in-hospital mortality and mortality, Barthel Index, and self-reported health status measures at 90 days. Results- The overall study cohort comprised 1509 nonsmokers and 1423 ever-smokers (841 former, 577 current, 5 unknown). No difference in primary outcome was observed between nonsmokers versus ever-smokers (adjusted odds ratio [aOR], 1.041; 95% CI, 0.904-1.199; P=0.577). No differences in primary outcome were observed between former (aOR, 0.932; 95% CI, 0.791-1.178; P=0.399) or current smokers (aOR, 1.178; 95% CI, 0.970-1.431; P=0.098) versus nonsmokers. Subgroup analyses by race/ethnicity demonstrated no differences in primary outcome when former and current smokers were compared with nonsmokers. Former, but not current, smokers had a lower in-hospital mortality rate (aOR, 0.695; 95% CI, 0.500-0.968; P=0.031), which was only observed in Hispanics (aOR, 0.533; 95% CI, 0.309-0.921; P=0.024). Differences in self-reported health status measures were only observed in whites. Conclusions- Cigarette smoking history does not seem to provide a beneficial effect on 90-day functional outcome in patients with ICH.
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Affiliation(s)
- Ching-Jen Chen
- Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia
| | - Dale Ding
- Department of Neurosurgery, University of Louisville, Louisville, Kentucky
| | - Natasha Ironside
- Department of Neurosurgery, NewYork-Presbyterian/Columbia University Medical Center, New York, New York
| | - Thomas J. Buell
- Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia
| | - Andrew M. Southerland
- Department of Neurology and Public Health Sciences, University of Virginia, Charlottesville, Virginia
| | - Sebastian Koch
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida
| | - Matthew Flaherty
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Daniel Woo
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Bradford B. Worrall
- Department of Neurology and Public Health Sciences, University of Virginia, Charlottesville, Virginia
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Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY. Signal Transducer and Activator of Transcription (STATs) Proteins in Cancer and Inflammation: Functions and Therapeutic Implication. Front Oncol 2019; 9:48. [PMID: 30847297 PMCID: PMC6393348 DOI: 10.3389/fonc.2019.00048] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 01/17/2019] [Indexed: 01/10/2023] Open
Abstract
Signal Transducer and Activator of Transcription (STAT) pathway is connected upstream with Janus kinases (JAK) family protein and capable of integrating inputs from different signaling pathways. Each family member plays unique functions in signal transduction and crucial in mediating cellular responses to different kind of cytokines. STAT family members notably STAT3 and STAT5 have been involved in cancer progression whereas STAT1 plays opposite role by suppressing tumor growth. Persistent STAT3/5 activation is known to promote chronic inflammation, which increases susceptibility of healthy cells to carcinogenesis. Here, we review the role of STATs in cancers and inflammation while discussing current therapeutic implications in different cancers and test models, especially the delivery of STAT3/5 targeting siRNA using nanoparticulate delivery system.
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Affiliation(s)
- Chin-Yap Loh
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Aditya Arya
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Ahmed Fadhil Naema
- Center of Biotechnology Researches, University of Al-Nahrain, Baghdad, Iraq
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
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Quik M, Boyd JT, Bordia T, Perez X. Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders. Nicotine Tob Res 2019; 21:357-369. [PMID: 30137517 PMCID: PMC6379038 DOI: 10.1093/ntr/nty063] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 03/28/2018] [Indexed: 12/18/2022]
Abstract
Emerging studies indicate that striatal cholinergic interneurons play an important role in synaptic plasticity and motor control under normal physiological conditions, while their disruption may lead to movement disorders. Here we discuss the involvement of the cholinergic system in motor dysfunction, with a focus on the role of the nicotinic cholinergic system in Parkinson's disease and drug-induced dyskinesias. Evidence for a role for the striatal nicotinic cholinergic system stems from studies showing that administration of nicotine or nicotinic receptor drugs protects against nigrostriatal degeneration and decreases L-dopa-induced dyskinesias. In addition, nicotinic receptor drugs may ameliorate tardive dyskinesia, Tourette's syndrome and ataxia, although further study is required to understand their full potential in the treatment of these disorders. A role for the striatal muscarinic cholinergic system in movement disorders stems from studies showing that muscarinic receptor drugs acutely improve Parkinson's disease motor symptoms, and may reduce dyskinesias and dystonia. Selective stimulation or lesioning of striatal cholinergic interneurons suggests they are primary players in this regulation, although multiple central nervous systems appear to be involved. IMPLICATIONS Accumulating data from preclinical studies and clinical trials suggest that drugs targeting CNS cholinergic systems may be useful for symptomatic treatment of movement disorders. Nicotinic cholinergic drugs, including nicotine and selective nAChR receptor agonists, reduce L-dopa-induced dyskinesias, as well as antipsychotic-induced tardive dyskinesia, and may be useful in Tourette's syndrome and ataxia. Subtype selective muscarinic cholinergic drugs may also provide effective therapies for Parkinson's disease, dyskinesias and dystonia. Continued studies/trials will help address this important issue.
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Affiliation(s)
- Maryka Quik
- Center for Health Sciences, SRI International, Menlo Park, CA
| | - James T Boyd
- University of Vermont Medical Center Neurology, Burlington, VT
| | - Tanuja Bordia
- Center for Health Sciences, SRI International, Menlo Park, CA
| | - Xiomara Perez
- Center for Health Sciences, SRI International, Menlo Park, CA
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Stegemann A, Böhm M. Tropisetron via α7 nicotinic acetylcholine receptor suppresses tumor necrosis factor-α-mediated cell responses of human keratinocytes. Exp Dermatol 2019; 28:276-282. [DOI: 10.1111/exd.13883] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 12/17/2018] [Accepted: 01/11/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Agatha Stegemann
- Department of Dermatology; University of Münster; Münster Germany
| | - Markus Böhm
- Department of Dermatology; University of Münster; Münster Germany
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Abstract
Surgery and other invasive procedures, which are routinely performed during general anesthesia, may induce an inflammatory response in the patient. This inflammatory response is an inherent answer of the body to the intervention and can be both beneficial and potentially harmful. The immune system represents a unique evolutionary achievement equipping higher organisms with an effective defense mechanism against exogenous pathogens. However, not only bacteria might evoke an immune response but also other noninfectious stimuli like the surgical trauma or mechanical ventilation may induce an inflammatory response of varying degree. In these cases, the immune system activation is not always beneficial for the patients and might carry the risk of concomitant, harmful effects on host cells, tissues, or even whole organ systems. Research over the past decades has contributed substantial information in which ways surgical patients may be affected by inflammatory reactions. Modulations of the patient's immune system may be evoked by the use of anesthetic agents, the nature of surgical trauma and the use of any supportive therapy during the perioperative period. The effects on the patient may be manifold, including various proinflammatory effects. This review focuses on the causes and effects of inflammation in the perioperative period. In addition, we also highlight possible approaches by which inflammation in the perioperative may be modulated in the future.
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Affiliation(s)
- Jan Rossaint
- From the Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
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Shimizu R, Ibaragi S, Eguchi T, Kuwajima D, Kodama S, Nishioka T, Okui T, Obata K, Takabatake K, Kawai H, Ono K, Okamoto K, Nagatsuka H, Sasaki A. Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma. Int J Oncol 2018; 54:283-294. [PMID: 30431077 DOI: 10.3892/ijo.2018.4631] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 10/24/2018] [Indexed: 12/20/2022] Open
Abstract
Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p‑EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non‑neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti‑cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine‑nAChR signaling to metastasize and acquire resistance to anti‑cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti‑EGFR‑therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p‑EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab‑inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p‑EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p‑EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance.
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Affiliation(s)
- Rieko Shimizu
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Soichiro Ibaragi
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Takanori Eguchi
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Daisuke Kuwajima
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Shinichi Kodama
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Takashi Nishioka
- Department of Oral Diagnosis, Tohoku University Graduate School of Dentistry, Sendai 980‑8575, Japan
| | - Tatsuo Okui
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Kyoichi Obata
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Kisho Ono
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Kuniaki Okamoto
- Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Akira Sasaki
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700‑8525, Japan
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Proietti S, Catizone A, Masiello MG, Dinicola S, Fabrizi G, Minini M, Ricci G, Verna R, Reiter RJ, Cucina A, Bizzarri M. Increase in motility and invasiveness of MCF7 cancer cells induced by nicotine is abolished by melatonin through inhibition of ERK phosphorylation. J Pineal Res 2018; 64:e12467. [PMID: 29338098 DOI: 10.1111/jpi.12467] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 01/04/2018] [Indexed: 01/18/2023]
Abstract
Through activation of the ERK pathway, nicotine, in both normal MCF-10A and low-malignant breast cancer cells (MCF7), promotes increased motility and invasiveness. Melatonin antagonizes both these effects by inhibiting almost completely ERK phosphorylation. As melatonin has no effect on nonstimulated cells, it is likely that melatonin can counteract ERK activation only downstream of nicotine-induced activation. This finding suggests that melatonin hampers ERK phosphorylation presumably by targeting a still unknown intermediate factor that connects nicotine stimulation to ERK phosphorylation. Furthermore, downstream of ERK activation, melatonin significantly reduces fascin and calpain activation while restoring normal vinculin levels. Melatonin also counteracts nicotine effects by reshaping the overall cytoskeleton architecture and abolishing invasive membrane protrusion. In addition, melatonin decreases nicotine-dependent ROCK1/ROCK2 activation, thus further inhibiting cell contractility and motility. Melatonin actions are most likely attributable to ERK inhibition, although melatonin could display other ERK-independent effects, namely through a direct modulation of additional molecular and structural factors, including coronin, cofilin, and cytoskeleton components.
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Affiliation(s)
- Sara Proietti
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
- Systems Biology Group, Rome, Italy
| | - Angela Catizone
- Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy
| | - Maria Grazia Masiello
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
- Systems Biology Group, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Simona Dinicola
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
- Systems Biology Group, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Gianmarco Fabrizi
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
- Systems Biology Group, Rome, Italy
| | - Mirko Minini
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
- Systems Biology Group, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Giulia Ricci
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Roberto Verna
- Systems Biology Group, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Russel J Reiter
- Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA
| | - Alessandra Cucina
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
- Systems Biology Group, Rome, Italy
- Azienda Policlinico Umberto I, Rome, Italy
| | - Mariano Bizzarri
- Systems Biology Group, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
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Jin T, Hao J, Fan D. Nicotine induces aberrant hypermethylation of tumor suppressor genes in pancreatic epithelial ductal cells. Biochem Biophys Res Commun 2018; 499:934-940. [PMID: 29626481 DOI: 10.1016/j.bbrc.2018.04.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 04/03/2018] [Indexed: 01/14/2023]
Abstract
Tobacco smoking is an independent risk factor for the initiation of pancreatic cancer (PC). Hypermethylation of tumor suppressor genes has been demonstrated to be associated with smoking. This study aimed to find the relationship between nicotine exposure and hypermethylation of tumor suppressor genes in normal pancreatic epithelial cells. Human pancreatic epithelial cells ware cultured exposing to nicotine and the methylation status of tumor suppressor genes were detected. Proenkephalin (PENK) was chosen as the target gene and methylation level of PENK promoter region was measured. Expression of DNA methyltransferase (DNMT), nicotine acetylcholine receptor (α7nAChR) and signaling pathway downstream were analyzed. Nicotine induces overexpression of DNMT3A and 3B, and methylated-inactivation of PENK gene in normal pancreatic epithelial cells. An activation of α7nAChR and MAPK signaling pathway has been detected in the nicotine-treated group. Demethylated drug, antagonist of α7nAChR and inhibitor of p38 MAPK is verified to attenuate the overexpression of DNMTs stimulated by nicotine as well as inhibit aberrant hypermethylation-related silence of PENK gene. Nicotine stimulation can induce aberrant hypermethylation of tumor suppressor genes by α7nAChR and MAPK signaling pathway-mediated up-regulation of DNMTs in pancreatic epithelial cells, thus we can provide epigenetic evidence of the mechanisms by which smoking causes pancreatic cancer and find new therapeutic target.
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Affiliation(s)
- Tong Jin
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
| | - Daiming Fan
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
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43
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More SV, Choi DK. Emerging preclinical pharmacological targets for Parkinson's disease. Oncotarget 2018; 7:29835-63. [PMID: 26988916 PMCID: PMC5045437 DOI: 10.18632/oncotarget.8104] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 02/08/2016] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) is a progressive neurological condition caused by the degeneration of dopaminergic neurons in the basal ganglia. It is the most prevalent form of Parkinsonism, categorized by cardinal features such as bradykinesia, rigidity, tremors, and postural instability. Due to the multicentric pathology of PD involving inflammation, oxidative stress, excitotoxicity, apoptosis, and protein aggregation, it has become difficult to pin-point a single therapeutic target and evaluate its potential application. Currently available drugs for treating PD provide only symptomatic relief and do not decrease or avert disease progression resulting in poor patient satisfaction and compliance. Significant amount of understanding concerning the pathophysiology of PD has offered a range of potential targets for PD. Several emerging targets including AAV-hAADC gene therapy, phosphodiesterase-4, potassium channels, myeloperoxidase, acetylcholinesterase, MAO-B, dopamine, A2A, mGlu5, and 5-HT-1A/1B receptors are in different stages of clinical development. Additionally, alternative interventions such as deep brain stimulation, thalamotomy, transcranial magnetic stimulation, and gamma knife surgery, are also being developed for patients with advanced PD. As much as these therapeutic targets hold potential to delay the onset and reverse the disease, more targets and alternative interventions need to be examined in different stages of PD. In this review, we discuss various emerging preclinical pharmacological targets that may serve as a new promising neuroprotective strategy that could actually help alleviate PD and its symptoms.
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Affiliation(s)
- Sandeep Vasant More
- Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, South Korea
| | - Dong-Kug Choi
- Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, South Korea
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Bagdas D, Gurun MS, Flood P, Papke RL, Damaj MI. New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on α7 nAChRs. Curr Neuropharmacol 2018; 16:415-425. [PMID: 28820052 PMCID: PMC6018191 DOI: 10.2174/1570159x15666170818102108] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 06/20/2017] [Accepted: 08/16/2017] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Nicotine and nicotinic acetylcholine receptors (nAChRs) have been explored for the past three decades as targets for pain control. The aim of this review is to introduce readers particularly to α7 nAChRs in a perspective of pain and its modulation. METHODS Developments for α7 nAChR modulators and recent animal studies related to pain are reviewed. RESULTS Accumulating evidences suggest that selective ligands for α7 nAChRs hold promise in the treatment of chronic pain conditions as they lack many of side effects associated with other nicotinic receptor types. CONCLUSION This review provides the reader recent insights on α7 nAChRs from structure and function to the latest findings on the pharmacology and therapeutic targeting of these receptors for the treatment of pain and inflammation.
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Affiliation(s)
- Deniz Bagdas
- Address correspondence to this author at the Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613; Tel/Fax: +1-804-828-9256; E-mail:
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Lu XX, Hong ZQ, Tan Z, Sui MH, Zhuang ZQ, Liu HH, Zheng XY, Yan TB, Geng DF, Jin DM. Nicotinic Acetylcholine Receptor Alpha7 Subunit Mediates Vagus Nerve Stimulation-Induced Neuroprotection in Acute Permanent Cerebral Ischemia by a7nAchR/JAK2 Pathway. Med Sci Monit 2017; 23:6072-6081. [PMID: 29274273 PMCID: PMC5747934 DOI: 10.12659/msm.907628] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Background The role of nicotinic acetylcholine receptor alpha7 subunit (a7nAchR) in the treatment of acute cerebral ischemia by VNS has not been thoroughly clarified to date. Therefore, this study aimed to investigate the specific role of a7nAchR and explore whether this process is involved in the mechanisms of VNS-induced neuroprotection in rats undergoing permanent middle cerebral artery occlusion (PMCAO) surgery. Material/Methods Rats received a7nAChR antagonist (A) or antagonist placebo injection for control (AC), followed by PMCAO and VNS treatment, whereas the a7nAChR agonist (P) was utilized singly without VNS treatment but only with PMCAO pretreatment. The rats were randomly divided into 6 groups: sham PMCAO, PMCAO, PMCAO+VNS, PMCAO+VNS+A, PMCAO+VNS+AC, and PMCAO+P. Neurological function and cerebral infarct volume were measured to evaluate the level of brain injury at 24 h after PMCAO or PMCAO-sham. Moreover, the related proteins levels of a7nAChR, p-JAK2, and p-STAT3 in the ischemic penumbra were assessed by Western blot analysis. Results Rats pretreated with VNS had significantly improved neurological function and reduced cerebral infarct volume after PMCAO injury (p<0.05). In addition, VNS enhanced the levels of a7nAchR, p-JAK2, and p-STAT3 in the ischemic penumbra (p<0.05). However, inhibition of a7nAchR not only attenuated the beneficial neuroprotective effects induced by VNS, but also decreased levels of p-JAK2 and p-STAT3. Strikingly, pharmacological activation of a7nAchR can partially substitute for VNS-induced beneficial neurological protection. Conclusions These results suggest that a7nAchR is a pivotal mediator of VNS-induced neuroprotective effects on PMCAO injury, which may be related to suppressed inflammation via activation of the a7nAchR/JAK2 anti-inflammatory pathway.
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Affiliation(s)
- Xin-Xin Lu
- Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Department of Rehabilitation Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - Zhong-Qiu Hong
- Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland)
| | - Zhi Tan
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland)
| | - Ming-Hong Sui
- Department of Rehabilitation Medicine, Shenzhen Nanshan People's Hospital (The Sixth People's Hospital of Shenzhen), Shenzhen University, Shenzhen, Guangdong, China (mainland)
| | - Zhi-Qiang Zhuang
- Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Engineering Technology Research Center for Rehabilitation and Elderly Care, Guangdong, China (mainland)
| | - Hui-Hua Liu
- Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Engineering Technology Research Center for Rehabilitation and Elderly Care, Guangdong, China (mainland)
| | - Xiu-Yuan Zheng
- Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Engineering Technology Research Center for Rehabilitation and Elderly Care, Guangdong, China (mainland)
| | - Tie-Bin Yan
- Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Engineering Technology Research Center for Rehabilitation and Elderly Care, Guangdong, China (mainland)
| | - Deng-Feng Geng
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland)
| | - Dong-Mei Jin
- Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Engineering Technology Research Center for Rehabilitation and Elderly Care, Guangdong, China (mainland)
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Yan Y, Su C, Hang M, Huang H, Zhao Y, Shao X, Bu X. Recombinant Newcastle disease virus rL-RVG enhances the apoptosis and inhibits the migration of A549 lung adenocarcinoma cells via regulating alpha 7 nicotinic acetylcholine receptors in vitro. Virol J 2017; 14:190. [PMID: 28974241 PMCID: PMC5627431 DOI: 10.1186/s12985-017-0852-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 09/20/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The aim of this study were to investigate the possible pro-apoptotic mechanisms of the recombinant Newcastle disease virus (NDV) strain rL-RVG, which expresses the rabies virus glycoprotein, in A549 lung adenocarcinoma cells via the regulation of alpha 7 nicotinic acetylcholine receptors (α7 nAChRs) and to analyze the relationships between α7 nAChR expression in lung cancer and the clinical pathological features. METHODS α7 nAChR expression in A549, LΑ795, and small-cell lung carcinoma (SCLC) cells, among others, was detected using reverse transcription polymerase chain reaction (RT-PCR). The optimal α7 nAChR antagonist and agonist concentrations for affecting A549 lung adenocarcinoma cells were detected using MTT assays. The α7 nAChR expression in A549 cells after various treatments was assessed by Western blot, immunofluorescence and RT-PCR analyses. Apoptosis in the various groups was also monitored by Western blot and TUNEL assays, followed by the detection of cell migration via transwell and scratch tests. Furthermore, α7 nAChR expression was examined by immunohistochemistry in lung cancer tissue samples from 130 patients and 40 pericancerous tissue samples, and the apoptotis in lung adenocarcinoma tissue was detected by Tunel assay, Then, the expression levels and clinicopathological characteristics were analyzed. RESULTS Of the A549, LΑ795, SCLC and U251 cell lines, the A549 cells exhibited the highest α7 nAChR expression. The cells infected with rL-RVG exhibited high RVG gene and protein expression. The rL-RVG group exhibited weaker α7 nAChR expression compared with the methyllycaconitine citrate hydrate (MLA, an α7 nAChR antagonist) and NDV groups. At the same time, the MLA and rL-RVG treatments significantly inhibited proliferation and migration and promoted apoptosis in the lung cancer cells (P < 0.05). The expression of α7 nAChR was upregulated in lung cancer tissue compared with pericancerous tissue (P = 0.000) and was significantly related to smoking, clinical tumor-node-metastases stage, and histological differentiation (P < 0.05). The AI in lung adenocarcinoma tissue in high-medium differentiation group was lower than that in low differentiation group (p < 0.01). CONCLUSIONS An antagonist of α7 nAChR may be used as a molecular target for lung adenocarcinoma therapy. Recombinant NDV rL-RVG enhances the apoptosis and inhibits the migration of A549 lung adenocarcinoma cells by regulating α7 nAChR signaling pathways.
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Affiliation(s)
- Yulan Yan
- Department of Respiratory Medicine, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu 212002 People’s Republic of China
| | - Chunxiang Su
- Department of Respiratory Medicine, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu 212002 People’s Republic of China
| | - Min Hang
- Department of Internal Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013 People’s Republic of China
| | - Hua Huang
- Department of Internal Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013 People’s Republic of China
| | - Yinghai Zhao
- Department of Internal Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013 People’s Republic of China
| | - Xiaomei Shao
- Department of Internal Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013 People’s Republic of China
| | - Xuefeng Bu
- Department of General Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu 212002 People’s Republic of China
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Sun HJ, Jia YF, Ma XL. Alpha5 Nicotinic Acetylcholine Receptor Contributes to Nicotine-Induced Lung Cancer Development and Progression. Front Pharmacol 2017; 8:573. [PMID: 28878681 PMCID: PMC5572410 DOI: 10.3389/fphar.2017.00573] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 08/09/2017] [Indexed: 12/14/2022] Open
Abstract
Nicotine and nicotinic acetylcholine receptors (nAChRs) are considered to be involved in lung cancer risk, onset and progression, but their precise physiological roles in these contexts remain unclear. Our previous studies suggested that α5-nAChR mediates nicotine-induced lung cancer cell proliferation, migration, and invasion in vitro. In this study, we aimed to determine the role of α5-nAChR in the development and progression of non-small cell lung cancer (NSCLC). Our microarray results reveal that knockdown of the CHRNA5 gene encoding α5-nAChR significantly modulates key pathways including the cell cycle, DNA replication, pathway in cancer. α5-nAChR knockdown in cultured A549 cells affected cell cycle distribution, apoptosis, and cyclin expression. In vivo, α5-nAChR silencing inhibited the growth of lung tumors, especially in the context of nicotine exposure. Importantly, α5-nAChR expression in patient tumors correlated with the primary T stage, N stage, and reduced survival time. These results reveal that α5-nAChR silencing inhibits the progression of nicotine-related NSCLC, making this receptor a potential pharmacological target for the treatment of nicotine-related lung carcinogenesis.
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Affiliation(s)
- Hai-Ji Sun
- Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Sciences, Shandong Normal UniversityJinan, China
| | - Yan-Fei Jia
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong UniversityJinan, China
| | - Xiao-Li Ma
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong UniversityJinan, China
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Zhang Y, Jia Y, Li P, Li H, Xiao D, Wang Y, Ma X. Reciprocal activation of α5-nAChR and STAT3 in nicotine-induced human lung cancer cell proliferation. J Genet Genomics 2017; 44:355-362. [PMID: 28750889 DOI: 10.1016/j.jgg.2017.03.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 03/02/2017] [Accepted: 03/17/2017] [Indexed: 01/26/2023]
Abstract
Cigarette smoking is the top environmental risk factor for lung cancer. Nicotine, the addictive component of cigarettes, induces lung cancer cell proliferation, invasion and migration via the activation of nicotinic acetylcholine receptors (nAChRs). Genome-wide association studies (GWAS) show that CHRNA5 gene encoding α5-nAChR is especially relevant to lung cancer. However, the mechanism of this subunit in lung cancer is not clear. In the present study, we demonstrate that the expression of α5-nAChR is correlated with phosphorylated STAT3 (pSTAT3) expression, smoking history and lower survival of non-small cell lung cancer (NSCLC) samples. Nicotine increased the levels of α5-nAChR mRNA and protein in NSCLC cell lines and activated the JAK2/STAT3 signaling cascade. Nicotine-induced activation of JAK2/STAT3 signaling was inhibited by the silencing of α5-nAChR. Characterization of the CHRNA5 promoter revealed four STAT3-response elements. ChIP assays confirmed that the CHRNA5 promoter contains STAT3 binding sites. By silencing STAT3 expression, nicotine-induced upregulation of α5-nAChR was suppressed. Downregulation of α5-nAChR and/or STAT3 expression inhibited nicotine-induced lung cancer cell proliferation. These results suggest that there is a feedback loop between α5-nAChR and STAT3 that contributes to the nicotine-induced tumor cell proliferation, which indicates that α5-nAChR is an important therapeutic target involved in tobacco-associated lung carcinogenesis.
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Affiliation(s)
- Yao Zhang
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250100, China
| | - Yanfei Jia
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250100, China
| | - Ping Li
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250100, China
| | - Huanjie Li
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250100, China; State Key Laboratory of Microbial Technology, Shandong University, Jinan 250100, China
| | - Dongjie Xiao
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250100, China
| | - Yunshan Wang
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250100, China
| | - Xiaoli Ma
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250100, China.
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Snail-Modulated MicroRNA 493 Forms a Negative Feedback Loop with the Insulin-Like Growth Factor 1 Receptor Pathway and Blocks Tumorigenesis. Mol Cell Biol 2017; 37:MCB.00510-16. [PMID: 27956702 DOI: 10.1128/mcb.00510-16] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/06/2016] [Indexed: 12/15/2022] Open
Abstract
In this study, we have identified one microRNA, microRNA 493 (miR-493), which could simultaneously and directly regulate multiple genes downstream of the insulin-like growth factor 1 receptor (IGF1R) pathway, including IGF1R, by binding with complementary sequences in the 3' untranslated region (UTR) of mRNAs of IGF1R, insulin receptor substrate 1 (IRS1), and mitogen-activated protein kinase 1 (MAPK1), thereby potentiating their inhibitory function at multiple levels in development and progression of cancers. This binding was further confirmed by pulldown of miR with AGO-2 antibody. Further, results from head and neck samples showed that miR-493 levels were significantly downregulated in tumors, with a concomitant increase in the expression of IGF1R and key downstream effectors. Functional studies from miR-493 overexpression cells and nude-mouse models revealed the tumor suppressor functions of miR-493. Regulation studies revealed that Snail binds to the miR-493 promoter and represses it. We found the existence of a dynamic negative feedback loop in the regulation of IGF1R and miR-493 mediated via Snail. Our study showed that nicotine treatment significantly decreases the levels of miR-493-with a concomitant increase in the levels of Snail-an indication of progression of cells toward tumorigenesis, reestablishing the role of tobacco as a major risk factor for head and neck cancers and elucidating the mechanism behind nicotine-mediated tumorigenesis.
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Tan MS, Tan JW, Chang SW, Yap HJ, Abdul Kareem S, Zain RB. A genetic programming approach to oral cancer prognosis. PeerJ 2016; 4:e2482. [PMID: 27688975 PMCID: PMC5036111 DOI: 10.7717/peerj.2482] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 08/24/2016] [Indexed: 11/20/2022] Open
Abstract
Background The potential of genetic programming (GP) on various fields has been attained in recent years. In bio-medical field, many researches in GP are focused on the recognition of cancerous cells and also on gene expression profiling data. In this research, the aim is to study the performance of GP on the survival prediction of a small sample size of oral cancer prognosis dataset, which is the first study in the field of oral cancer prognosis. Method GP is applied on an oral cancer dataset that contains 31 cases collected from the Malaysia Oral Cancer Database and Tissue Bank System (MOCDTBS). The feature subsets that is automatically selected through GP were noted and the influences of this subset on the results of GP were recorded. In addition, a comparison between the GP performance and that of the Support Vector Machine (SVM) and logistic regression (LR) are also done in order to verify the predictive capabilities of the GP. Result The result shows that GP performed the best (average accuracy of 83.87% and average AUROC of 0.8341) when the features selected are smoking, drinking, chewing, histological differentiation of SCC, and oncogene p63. In addition, based on the comparison results, we found that the GP outperformed the SVM and LR in oral cancer prognosis. Discussion Some of the features in the dataset are found to be statistically co-related. This is because the accuracy of the GP prediction drops when one of the feature in the best feature subset is excluded. Thus, GP provides an automatic feature selection function, which chooses features that are highly correlated to the prognosis of oral cancer. This makes GP an ideal prediction model for cancer clinical and genomic data that can be used to aid physicians in their decision making stage of diagnosis or prognosis.
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Affiliation(s)
- Mei Sze Tan
- Bioinformatics Program, Institute of Biological Sciences, Faculty of Science, University of Malaya , Kuala Lumpur , Malaysia
| | - Jing Wei Tan
- Bioinformatics Program, Institute of Biological Sciences, Faculty of Science, University of Malaya , Kuala Lumpur , Malaysia
| | - Siow-Wee Chang
- Bioinformatics Program, Institute of Biological Sciences, Faculty of Science, University of Malaya , Kuala Lumpur , Malaysia
| | - Hwa Jen Yap
- Department of Mechanical Engineering, Faculty of Engineering, University of Malaya , Kuala Lumpur , Malaysia
| | - Sameem Abdul Kareem
- Department of Artificial Intelligence, Faculty of Computer Science & Information Technology, University of Malaya , Kuala Lumpur , Malaysia
| | - Rosnah Binti Zain
- Oral Cancer Research & Coordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya , Kuala Lumpur , Malaysia
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