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Wang X, Luo H, Peng X, Chen J. Spider and scorpion knottins targeting voltage-gated sodium ion channels in pain signaling. Biochem Pharmacol 2024; 227:116465. [PMID: 39102991 DOI: 10.1016/j.bcp.2024.116465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/07/2024]
Abstract
In sensory neurons that transmit pain signals, whether acute or chronic, voltage-gated sodium channels (VGSCs) are crucial for regulating excitability. NaV1.1, NaV1.3, NaV1.6, NaV1.7, NaV1.8, and NaV1.9 have been demonstrated and defined their functional roles in pain signaling based on their biophysical properties and distinct patterns of expression in each subtype of sensory neurons. Scorpions and spiders are traditional Chinese medicinal materials, belonging to the arachnid class. Most of the studied species of them have evolved venom peptides that exhibit a wide variety of knottins specifically targeting VGSCs with subtype selectivity and conformational specificity. This review provides an overview on the exquisite knottins from scorpion and spider venoms targeting pain-related NaV channels, describing the sequences and the structural features as well as molecular determinants that influence their selectivity on special subtype and at particular conformation, with an aim for the development of novel research tools on NaV channels and analgesics with minimal adverse effects.
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Affiliation(s)
- Xiting Wang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Huan Luo
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Xiaozhen Peng
- School of Public Health & Laboratory Medicine, Hunan University of Medicine, Huaihua 418000, China.
| | - Jinjun Chen
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan 410128, China; Hunan Provincial Engineering Technology Research Center for Cell Mechanics and Function Analysis, Changsha 418000, China.
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Zeng J, Gao WW, Yang H, Wang YN, Mei Y, Liu TT, Wang M, Tang L, Ma DC, Li W. Sodium tanshinone IIA sulfonate suppresses microglia polarization and neuroinflammation possibly via regulating miR-125b-5p/STAT3 axis to ameliorate neuropathic pain. Eur J Pharmacol 2024; 972:176523. [PMID: 38552937 DOI: 10.1016/j.ejphar.2024.176523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 03/05/2024] [Accepted: 03/21/2024] [Indexed: 04/20/2024]
Abstract
The spinal cord microglia play a pivotal role in neuroinflammation and neuropathic pain (NP). Sodium tanshinone IIA sulfonate (STS), a derivative of tanshinone IIA, has anti-inflammatory and anti-hyperalgesic effects. However, its underlying mechanism in NP remains unclear. This study aimed to investigate the effect of STS and elucidate possible mechanisms in a rat model of spared nerve injury. In vivo experiments, STS and AG490 were administered intraperitoneally once daily for 14 consecutive days after surgery. The results showed that the expression of miR-125b-5p in the spinal dorsal horn was substantially reduced, whereas signal transducer and activator of transcription 3 (STAT3) signaling was increased. After treatment with STS, the mechanical thresholds, expression of miR-125b-5p, and microglial M2 marker such as Arg-1 in the spinal cord horn increased significantly, whereas multiple pro-inflammatory cytokines and apoptosis were significantly reduced. Moreover, STAT3 pathway-related proteins and expression of the microglial M1 marker, CD68, were appreciably inhibited. In vitro, lipopolysaccharide (LPS) was used to induce an inflammatory response in BV-2 microglial cells. STS pretreatment inhibited LPS-stimulated pro-inflammatory cytokine secretion, reduced STAT3 pathway related-proteins and apoptosis, increased miR-125b-5p and proopiomelanocortin expression, and enhanced microglia transformation from M1 to M2 phenotype in BV-2 cells. These effects were reversed after the inhibition of miR-125b-5p expression in BV-2 cells. A dual-luciferase reporter assay confirmed that STAT3 binds to miR-125b-5p. In summary, these results suggest that STS exerts anti-hyperalgesic and anti-neuroinflammatory effects in rats with NP possibly via the miR-125b-5p/STAT3 axis.
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Affiliation(s)
- Jie Zeng
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China.
| | - Wei-Wei Gao
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Hao Yang
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Ya-Nang Wang
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Yang Mei
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Ting-Ting Liu
- Department of Pain Medicine, Affiliated Shapingba Hospital, Chongqing University, Chongqing, China
| | - Min Wang
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Li Tang
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Dong-Chuan Ma
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Wei Li
- Department of Pain Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China.
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Kang T, Qin X, Chen Y, Yang Q. Systematic investigation of Radix Salviae for treating diabetic peripheral neuropathy disease based on network Pharmacology. World J Diabetes 2024; 15:945-957. [PMID: 38766429 PMCID: PMC11099361 DOI: 10.4239/wjd.v15.i5.945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/07/2024] [Accepted: 03/13/2024] [Indexed: 05/10/2024] Open
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus with limited available treatment options. Radix Salviae, a traditional Chinese herb, has shown promise in treating DPN, but its therapeutic mech-anisms have not been systematically investigated. AIM Radix Salviae (Danshen in pinin), a traditional Chinese medicine (TCM), is widely used to treat DPN in China. However, the mechanism through which Radix Salviae treats DPN remains unclear. Therefore, we aimed to explore the mechanism of action of Radix Salviae against DPN using network pharmacology. METHODS The active ingredients and target genes of Radix Salviae were screened using the TCM pharmacology database and analysis platform. The genes associated with DPN were obtained from the Gene Cards and OMIM databases, a drug-com-position-target-disease network was constructed, and a protein-protein inter-action network was subsequently constructed to screen the main targets. Gene Ontology (GO) functional annotation and pathway enrichment analysis were performed via the Kyoto Encyclopedia of Genes and Genomes (KEGG) using Bioconductor. RESULTS A total of 56 effective components, 108 targets and 4581 DPN-related target genes of Radix Salviae were screened. Intervention with Radix Salviae for DPN mainly involved 81 target genes. The top 30 major targets were selected for enrichment analysis of GO and KEGG pathways. CONCLUSION These results suggested that Radix Salviae could treat DPN by regulating the AGE-RAGE signaling pathway and the PI3K-Akt signaling pathway. Therefore, Danshen may affect DPN by regulating inflammation and apoptosis.
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Affiliation(s)
- Tao Kang
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
| | - Xiao Qin
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
| | - Yan Chen
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
| | - Qian Yang
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
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Wang Q, Ye Y, Yang L, Xiao L, Liu J, Zhang W, Du G. Painful diabetic neuropathy: The role of ion channels. Biomed Pharmacother 2024; 173:116417. [PMID: 38490158 DOI: 10.1016/j.biopha.2024.116417] [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: 11/30/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/17/2024] Open
Abstract
Painful diabetic neuropathy (PDN) is a common chronic complication of diabetes that causes neuropathic pain and negatively affects the quality of life. The management of PDN is far from satisfactory. At present, interventions are primarily focused on symptomatic treatment. Ion channel disorders are a major cause of PDN, and a complete understanding of their roles and mechanisms may provide better options for the clinical treatment of PDN. Therefore, this review summarizes the important role of ion channels in PDN and the current drug development targeting these ion channels.
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Affiliation(s)
- Qi Wang
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yifei Ye
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Linghui Yang
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Lifan Xiao
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Jin Liu
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Wensheng Zhang
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
| | - Guizhi Du
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
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Turnaturi R, Piana S, Spoto S, Costanzo G, Reina L, Pasquinucci L, Parenti C. From Plant to Chemistry: Sources of Antinociceptive Non-Opioid Active Principles for Medicinal Chemistry and Drug Design. Molecules 2024; 29:815. [PMID: 38398566 PMCID: PMC10892999 DOI: 10.3390/molecules29040815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Pain is associated with many health problems and a reduced quality of life and has been a common reason for seeking medical attention. Several therapeutics are available on the market, although side effects, physical dependence, and abuse limit their use. As the process of pain transmission and modulation is regulated by different peripheral and central mechanisms and neurotransmitters, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery due to their chemical structural variety and different analgesic mechanisms. Numerous studies suggested that some chemicals from medicinal plants could be alternative options for pain relief and management. Previously, we conducted a literature search aimed at identifying natural products interacting either directly or indirectly with opioid receptors. In this review, instead, we have made an excursus including active ingredients derived from plants whose mechanism of action appears from the literature to be other than the modulation of the opioid system. These substances could, either by themselves or through synthetic and/or semi-synthetic derivatives, be investigated in order to improve their pharmacokinetic characteristics and could represent a valid alternative to the opioid approach to pain therapy. They could also be the basis for the study of new mechanisms of action in the approach to this complex and disabling pathology.
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Affiliation(s)
- Rita Turnaturi
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; (R.T.); (S.P.)
| | - Silvia Piana
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; (R.T.); (S.P.)
| | - Salvatore Spoto
- Department of Drug and Health Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; (S.S.); (C.P.)
| | - Giuliana Costanzo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy;
| | - Lorena Reina
- Postgraduate School of Clinical Pharmacology and Toxicology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy;
| | - Lorella Pasquinucci
- Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; (R.T.); (S.P.)
| | - Carmela Parenti
- Department of Drug and Health Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; (S.S.); (C.P.)
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Leal-Cardoso JH, Ferreira-da-Silva FW, Coelho-de-Souza AN, da Silva-Alves KS. Diabetes-induced electrophysiological alterations on neurosomes in ganglia of peripheral nervous system. Biophys Rev 2023; 15:625-638. [PMID: 37681090 PMCID: PMC10480376 DOI: 10.1007/s12551-023-01094-1] [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: 04/11/2023] [Accepted: 06/30/2023] [Indexed: 09/09/2023] Open
Abstract
Diabetes mellitus (DM) leads to medical complications, the epidemiologically most important of which is diabetic peripheral neuropathy (DPN). Electrophysiology is a major component of neural functioning and several studies have been undertaken to elucidate the neural electrophysiological alterations caused by DM and their mechanisms of action. Due to the importance of electrophysiology for neuronal function, the review of the studies dealing predominantly with electrophysiological parameters and mechanisms in the neuronal somata of peripheral neural ganglia of diabetic animals during the last 45 years is here undertaken. These studies, using predominantly techniques of electrophysiology, most frequently patch clamp for voltage clamp studies of transmembrane currents through ionic channels, have investigated the experimental DPN. They also have demonstrated that various cellular and molecular mechanisms of action of diabetic physiopathology at the level of biophysical electrical parameters are affected in DPN. Thus, they have demonstrated that several passive and active transmembrane voltage parameters, related to neuronal excitability and neuronal functions, are altered in diabetes. The majority of the studies agreed that DM produces depolarization of the resting membrane potential; alters excitability, increasing and decreasing it in dorsal root ganglia (DRG) and in nodose ganglion, respectively. They have tried to relate these changes to sensorial alterations of DPN. Concerning ionic currents, predominantly studied in DRG, the most frequent finding was increases in Na+, Ca2+, and TRPV1 cation current, and decreases in K+ current. This review concluded that additional studies are needed before an understanding of the hierarchized, time-dependent, and integrated picture of the contribution of neural electrophysiological alterations to the DPN could be reached. DM-induced electrophysiological neuronal alterations that so far have been demonstrated, most of them likely important, are either consistent with the DPN symptomatology or suggest important directions for improvement of the elucidation of DPN physiopathology, which the continuation seems to us very relevant.
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Affiliation(s)
- José Henrique Leal-Cardoso
- Laboratory of Electrophysiology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700 Dr. Silas Munguba Avenue, Fortaleza, Ceará 60714-903 Brazil
| | - Francisco Walber Ferreira-da-Silva
- Laboratory of Electrophysiology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700 Dr. Silas Munguba Avenue, Fortaleza, Ceará 60714-903 Brazil
- Civil Engineering Department, State University of Vale do Acaraú, Sobral, Ceará Brazil
| | - Andrelina Noronha Coelho-de-Souza
- Laboratory of Electrophysiology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700 Dr. Silas Munguba Avenue, Fortaleza, Ceará 60714-903 Brazil
- Laboratory of Experimental Physiology, Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza, Ceará Brazil
| | - Kerly Shamyra da Silva-Alves
- Laboratory of Electrophysiology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700 Dr. Silas Munguba Avenue, Fortaleza, Ceará 60714-903 Brazil
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Brackx W, de Cássia Collaço R, Theys M, Cruyssen JV, Bosmans F. Understanding the physiological role of Na V1.9: Challenges and opportunities for pain modulation. Pharmacol Ther 2023; 245:108416. [PMID: 37061202 DOI: 10.1016/j.pharmthera.2023.108416] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/31/2023] [Accepted: 04/12/2023] [Indexed: 04/17/2023]
Abstract
Voltage-activated Na+ (NaV) channels are crucial contributors to rapid electrical signaling in the human body. As such, they are among the most targeted membrane proteins by clinical therapeutics and natural toxins. Several of the nine mammalian NaV channel subtypes play a documented role in pain or other sensory processes such as itch, touch, and smell. While causal relationships between these subtypes and biological function have been extensively described, the physiological role of NaV1.9 is less understood. Yet, mutations in NaV1.9 can cause striking disease phenotypes related to sensory perception such as loss or gain of pain and chronic itch. Here, we explore our current knowledge of the mechanisms by which NaV1.9 may contribute to pain and elaborate on the challenges associated with establishing links between experimental conditions and human disease. This review also discusses the lack of comprehensive insights into NaV1.9-specific pharmacology, an unfortunate situation since modulatory compounds may have tremendous potential in the clinic to treat pain or as precision tools to examine the extent of NaV1.9 participation in sensory perception processes.
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Affiliation(s)
- Wayra Brackx
- Molecular Physiology and Neurophysics Group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium
| | - Rita de Cássia Collaço
- Molecular Physiology and Neurophysics Group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium
| | - Margaux Theys
- Molecular Physiology and Neurophysics Group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium
| | - Jolien Vander Cruyssen
- Molecular Physiology and Neurophysics Group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium
| | - Frank Bosmans
- Molecular Physiology and Neurophysics Group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium.
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Zhong C, Lin Z, Ke L, Shi P, Li S, Huang L, Lin X, Yao H. Recent Research Progress (2015-2021) and Perspectives on the Pharmacological Effects and Mechanisms of Tanshinone IIA. Front Pharmacol 2021; 12:778847. [PMID: 34819867 PMCID: PMC8606659 DOI: 10.3389/fphar.2021.778847] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/26/2021] [Indexed: 12/15/2022] Open
Abstract
Tanshinone IIA (Tan IIA) is an important characteristic component and active ingredient in Salvia miltiorrhiza, and its various aspects of research are constantly being updated to explore its potential application. In this paper, we review the recent progress on pharmacological activities and the therapeutic mechanisms of Tan IIA according to literature during the years 2015-2021. Tan IIA shows multiple pharmacological effects, including anticarcinogenic, cardiovascular, nervous, respiratory, urinary, digestive, and motor systems activities. Tan IIA modulates multi-targets referring to Nrf2, AMPK, GSK-3β, EGFR, CD36, HO-1, NOX4, Beclin-1, TLR4, TNF-α, STAT3, Caspase-3, and bcl-2 proteins and multi-pathways including NF-κB, SIRT1/PGC1α, MAPK, SREBP-2/Pcsk9, Wnt, PI3K/Akt/mTOR pathways, TGF-β/Smad and Hippo/YAP pathways, etc., which directly or indirectly influence disease course. Further, with the reported targets, the potential effects and possible mechanisms of Tan IIA against diseases were predicted by bioinformatic analysis. This paper provides new insights into the therapeutic effects and mechanisms of Tan IIA against diseases.
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Affiliation(s)
- Chenhui Zhong
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Zuan Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Liyuan Ke
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Peiying Shi
- Department of Traditional Chinese Medicine Resource and Bee Products, College of Animal Sciences (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, China
| | - Shaoguang Li
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Liying Huang
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Xinhua Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
- Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou, China
| | - Hong Yao
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
- Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou, China
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Feng JH, Kim HY, Sim SM, Zuo GL, Jung JS, Hwang SH, Kwak YG, Kim MJ, Jo JH, Kim SC, Lim SS, Suh HW. The Anti-Inflammatory and the Antinociceptive Effects of Mixed Agrimonia pilosa Ledeb. and Salvia miltiorrhiza Bunge Extract. PLANTS 2021; 10:plants10061234. [PMID: 34204404 PMCID: PMC8234973 DOI: 10.3390/plants10061234] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/17/2022]
Abstract
Arthritis is a common condition that causes pain and inflammation in a joint. Previously, we reported that the mixture extract (ME) from Agrimonia pilosa Ledeb. (AP) and Salvia miltiorrhiza Bunge (SM) could ameliorate gout arthritis. In the present study, we aimed to investigate the potential anti-inflammatory and antinociceptive effects of ME and characterize the mechanism. We compared the anti-inflammatory and antinociceptive effects of a positive control, Perna canaliculus powder (PC). The results showed that one-off and one-week treatment of ME reduced the pain threshold in a dose-dependent manner (from 10 to 100 mg/kg) in the mono-iodoacetate (MIA)-induced osteoarthritis (OA) model. ME also reduced the plasma TNF-α, IL-6, and CRP levels. In LPS-stimulated RAW 264.7 cells, ME inhibited the release of NO, PGE2, LTB4, and IL-6, increased the phosphorylation of PPAR-γ protein, and downregulated TNF-α and MAPKs proteins expression in a concentration-dependent (from 1 to 100 µg/mL) manner. Furthermore, ME ameliorated the progression of ear edema in mice. In most of the experiments, ME-induced effects were almost equal to, or were higher than, PC-induced effects. Conclusions: The data presented here suggest that ME shows anti-inflammatory and antinociceptive activities, indicating ME may be a potential therapeutic for arthritis treatment.
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Affiliation(s)
- Jing-Hui Feng
- Department of Pharmacology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (J.-H.F.); (S.-M.S.)
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Hyun-Yong Kim
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
| | - Su-Min Sim
- Department of Pharmacology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (J.-H.F.); (S.-M.S.)
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Guang-Lei Zuo
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
| | - Jeon-Sub Jung
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Seung-Hwan Hwang
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
- R&D Center, Huons Co., Ltd., 55 Hanyangdaehak-ro, Ansan 15588, Gyeonggi-do, Korea
| | - Youn-Gil Kwak
- Research Institute, Huons Nature, Geumsan 32742, Choong-cheong Nam-do, Korea; (Y.-G.K.); (M.-J.K.); (J.-H.J.)
| | - Min-Jung Kim
- Research Institute, Huons Nature, Geumsan 32742, Choong-cheong Nam-do, Korea; (Y.-G.K.); (M.-J.K.); (J.-H.J.)
| | - Jeong-Hun Jo
- Research Institute, Huons Nature, Geumsan 32742, Choong-cheong Nam-do, Korea; (Y.-G.K.); (M.-J.K.); (J.-H.J.)
| | - Sung-Chan Kim
- Department of Biochemistry, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
| | - Soon-Sung Lim
- Department of Food Science and Nutrition, College of Natural Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (H.-Y.K.); (G.-L.Z.); (S.-H.H.)
- Correspondence: (S.-S.L.); (H.-W.S.); Tel.: +82-33-248-2133 (S.-S.L.); +82-33-248-2614 (H.-W.S.)
| | - Hong-Won Suh
- Department of Pharmacology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea; (J.-H.F.); (S.-M.S.)
- Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon 24252, Gangwon-do, Korea;
- Correspondence: (S.-S.L.); (H.-W.S.); Tel.: +82-33-248-2133 (S.-S.L.); +82-33-248-2614 (H.-W.S.)
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Zhou YQ, Mei W, Tian XB, Tian YK, Liu DQ, Ye DW. The therapeutic potential of Nrf2 inducers in chronic pain: Evidence from preclinical studies. Pharmacol Ther 2021; 225:107846. [PMID: 33819559 DOI: 10.1016/j.pharmthera.2021.107846] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/29/2021] [Indexed: 02/06/2023]
Abstract
Chronic pain remains an enormous health problem affecting approximatively 30% of the world's population. Opioids as the first line analgesics often leads to undesirable side effects when used long term. Therefore, novel therapeutic targets are urgently needed to the development of more efficacious analgesics. Substantial evidence indicates that excessive reactive oxygen species (ROS) are extremely important to the development of chronic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor regulating endogenous antioxidant defense. Emerging evidence suggests that Nrf2 and its downstream effectors are implicated in chronic inflammatory and neuropathic pain. Notably, controversial results have been reported regarding the expression of Nrf2 and its downstream targets in peripheral and central regions involved in pain transmission. However, our recent studies and results from other laboratories demonstrate that Nrf2 inducers exert potent analgesic effects in various murine models of chronic pain. In this review, we summarized and discussed the preclinical evidence demonstrating the therapeutic potential of Nrf2 inducers in chronic pain. These evidence indicates that Nrf2 activation are beneficial in chronic pain mostly by alleviating ROS-associated pathological processes. Overall, Nrf2-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.
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Affiliation(s)
- Ya-Qun Zhou
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wei Mei
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xue-Bi Tian
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yu-Ke Tian
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dai-Qiang Liu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Da-Wei Ye
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Tongji Shanxi Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, 030032, China; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Qian J, Cao Y, Zhang J, Li L, Wu J, Wei G, Yu J, Huo J. Tanshinone IIA induces autophagy in colon cancer cells through MEK/ERK/mTOR pathway. Transl Cancer Res 2020; 9:6919-6928. [PMID: 35117300 PMCID: PMC8797932 DOI: 10.21037/tcr-20-1963] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/14/2020] [Indexed: 12/19/2022]
Abstract
Background Colon cancer is a common malignancy of the digestive tract. The search for effective drugs to treat colon cancer has become the focus of current researches. Tanshinone IIA (Tan IIA) is a fat-soluble component extracted from tanshinone, a traditional Chinese medicine. Tan IIA can modulate the occurrence and development of tumors, but its effect on autophagy in colon cancer cells has not been reported. Methods Two types of colon cancer cell lines were selected and different concentrations of Tan IIA were used to treat cells at different time points. Cell Counting Kit-8 assay (CCK-8) was used to detect the effect of Tan IIA on cell proliferation; transmission electron microscopy was used to observe the formation of autophagosomes; reverse transcription-polymerase chain reaction (RT-qPCR) and western blot were used to detect the expression of autophagy related genes and proteins. Cell transfection was used to interfere with MEK (mitogen-activated extracellular signal-regulated kinase) expression, and RT-qPCR and western blot were used to detect the expression of MEK/ERK/mTOR pathway-related proteins. Results Tan IIA resulted in a significant reduction in the viability of the two kinds of colon cancer cells. The number of autophagosomes increased significantly after the treatment of Tan IIA into these cells. Addition of autophagy inhibitor 3-MA (3-Methyladenine) improved the increase of autophagosomes in cells induced by Tan IIA. At the same time, Tan IIA induced the expression of autophagy-related proteins in the two colon cancer cell lines. When Tan IIA induced autophagy in colon cancer cells, the expression of MEK/ERK/mTOR pathway-related proteins increased significantly. After interfering with the expression of MEK, the expression of autophagy decreased significantly, indicating that Tan IIA promoted autophagy of colon cancer cells through MEK/ERK/mTOR pathway. Conclusions Tan IIA stimulates autophagy in colon cancer cells through MEK/ERK/mTOR pathway, hence inhibiting the growth of colon cancer cells.
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Affiliation(s)
- Jun Qian
- Department of Diagnostics of Chinese Medicine, School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yi Cao
- Research Office of Herbal Literature, Institute of Literature in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Junfeng Zhang
- Department of Pathogen and Immunology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lingchang Li
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Wu
- Department of Public health, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guoli Wei
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jialin Yu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Leng J, Li X, Tian H, Liu C, Guo Y, Zhang S, Chu Y, Li J, Wang Y, Zhang L. Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway. BMC Complement Med Ther 2020; 20:126. [PMID: 32336289 PMCID: PMC7184706 DOI: 10.1186/s12906-020-02930-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/16/2020] [Indexed: 12/04/2022] Open
Abstract
Background Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. Diosgenin is a natural steroidal saponin with a variety of beneficial effects, including antidiabetic effects, and is a raw material for the synthesis of carrier hormones. In our study, we aimed to assess the antioxidant effects of diosgenin in diabetic mice. Methods Male C57 mice were fed a high-fat diet for 8 weeks and intraperitoneally injected with streptozotocin (STZ) at a dose of 100 mg/kg for 2 consecutive days. Eligible mice were divided into the normal control group (CON), diabetic group (DM), low-dose diosgenin (50 mg/kg) group (DIO50) and high-dose diosgenin (100 mg/kg) group (DIO100). Treatment was started 6 weeks after the induction of diabetes by STZ and continued for 8 weeks. Blood sugar and body weight were monitored dynamically. The behavioural effects of diosgenin were detected by a hot tail immersion test and paw tactile responses. HE staining was used to evaluate edema and degeneration of the sciatic nerve. The levels of SOD, MDA and GPx were tested according to the instructions of the respective kits. The levels of Nrf2, HO-1 and NQO1 were detected by immunofluorescence and Western blotting. Statistical analysis was performed using SPSS, and P < 0.05 was considered statistically significant. Results Diosgenin decreased the blood glucose levels and increased the body weight of diabetic mice. There was a significant increase in the tail withdrawal latency of diabetic animals, and mechanical hyperalgesia was significantly alleviated after diosgenin treatment. Histopathological micrographs of HE-stained sciatic nerves showed improvement after diosgenin treatment. Diosgenin attenuated the level of MDA but increased the activities of SOD and GPx. Diosgenin increased the expression of Nrf2, HO-1 and NQO1. Conclusions Our results demonstrate that diosgenin can ameliorate behavioural and morphological changes in DPN by reducing oxidative stress. The Nrf2/HO-1 signalling pathway was involved in its neuroprotective effects.
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Affiliation(s)
- Jinhong Leng
- Department of Endocrinology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, Liaoning, China
| | - Xiaohua Li
- Department of Traditional Chinese Medicine Clinical Endocrinology, Liaoning University of Traditional Chinese Medicine Graduate School, Shenyang, 110847, Liaoning, China
| | - He Tian
- Department of Histology and Embryology, School of Basic Medicine, Jinzhou Medical University, Jinzhou, 121000, Liaoning, China.
| | - Chang Liu
- Department of Endocrinology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, China.
| | - Yining Guo
- Department of Traditional Chinese Medicine Clinical Endocrinology, Liaoning University of Traditional Chinese Medicine Graduate School, Shenyang, 110847, Liaoning, China
| | - Su Zhang
- Department of Traditional Chinese Medicine Clinical Endocrinology, Liaoning University of Traditional Chinese Medicine Graduate School, Shenyang, 110847, Liaoning, China
| | - Yang Chu
- Department of Traditional Chinese Medicine Clinical Endocrinology, Liaoning University of Traditional Chinese Medicine Graduate School, Shenyang, 110847, Liaoning, China
| | - Jian Li
- Department of Traditional Chinese Medicine Clinical Endocrinology, Liaoning University of Traditional Chinese Medicine Graduate School, Shenyang, 110847, Liaoning, China
| | - Ying Wang
- Department of Traditional Chinese Medicine Clinical Endocrinology, Liaoning University of Traditional Chinese Medicine Graduate School, Shenyang, 110847, Liaoning, China
| | - Ling Zhang
- Department of Traditional Chinese Medicine Clinical Endocrinology, Liaoning University of Traditional Chinese Medicine Graduate School, Shenyang, 110847, Liaoning, China
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