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Liu S, Zhang T, Chen Z, Guo K, Zhao P. Structural characterization of Corydalis yanhusuo polysaccharides and its bioactivity in vitro. Int J Biol Macromol 2025; 306:141575. [PMID: 40023428 DOI: 10.1016/j.ijbiomac.2025.141575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
This study isolated and purified two polysaccharides, CYHSP-1 and CYHSP-2, from Corydalis yanhusuo, and investigated their structures and in vitro biological activities. The findings revealed that CYHSP-1 and CYHSP-2 possess average molecular weights of 97.17 and 23.48 kDa, respectively, indicating uniform molecular weight glucans. Structural characterization, utilizing techniques such as Fourier transform infrared spectroscopy (FT-IR) and methylation analysis, identified the presence of sugar units including α-1,4-Glc-(1→, α-1,4,6-Glc-(1→, α-1,6-Glc-(1→, and α-t-Glc-(1→. CYHSP-1 demonstrated superior radical scavenging activity and a more pronounced inhibitory effect on human hepatocellular carcinoma HepG2 cells compared to CYHSP-2. These results indicate the significant potential of these Corydalis yanhusuo-derived polysaccharides as natural antioxidants and anti-tumor agents.
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Affiliation(s)
- Simei Liu
- Shaanxi Key Laboratory of Traditional Chinese Pharmacy Foundation and New Drug Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an 712046, China
| | - Tingting Zhang
- Shaanxi Key Laboratory of Traditional Chinese Pharmacy Foundation and New Drug Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an 712046, China
| | - Zilong Chen
- China Food and Drug Control Center of Weinan Institute of Inspection and Research in Shaanxi Province, Weinan, Shaanxi 714000, China
| | - Ke Guo
- Shaanxi Key Laboratory of Traditional Chinese Pharmacy Foundation and New Drug Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an 712046, China
| | - Peng Zhao
- Shaanxi Key Laboratory of Traditional Chinese Pharmacy Foundation and New Drug Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an 712046, China.
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Chenchula S, Ghanta MK, Alhammadi M, Mohammed A, Anitha K, Nuthalapati P, Raju GSR, Huh YS, Bhaskar L. Phytochemical compounds for treating hyperuricemia associated with gout: a systematic review. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4779-4801. [PMID: 39636406 DOI: 10.1007/s00210-024-03686-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Gout is a prevalent metabolic disorder characterized by increased uric acid (UA) synthesis or decreased UA clearance from the bloodstream, leading to the formation of urate crystals in joints and surrounding tissues. Hyperuricemia (HUA), the underlying cause of gout, poses a growing challenge for healthcare systems in developed and developing countries. Currently, the most common therapeutic approaches for gouty HUA primarily involve the use of allopathic or modern medicine. However, these treatments are often accompanied by adverse effects and may not be universally effective for all patients. Therefore, this systematic review aims to provide a comprehensive outline of phytochemical compounds that have emerged as alternative treatments for HUA associated with gout and to examine their specific mechanisms of action. A systematic search was conducted to identify phytochemicals that have previously been evaluated for their effectiveness in reducing HUA. From a review of > 800 published articles, 100 studies reporting on 50 phytochemicals associated with the management of HUA and gout were selected for analysis. Experimental models were used to investigate the effects of these phytochemicals, many of which exhibited multiple mechanisms beneficial for managing HUA. This review offers valuable insights for identifying and developing novel compounds that are safer and more effective for treating HUA associated with gout.
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Affiliation(s)
- Santenna Chenchula
- Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Mohan Krishna Ghanta
- Department of Pharmacology, MVJ Medical College and Research Hospital, Bangalore, 562114, Karnataka, India
| | - Munirah Alhammadi
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon, 22212, Republic of Korea
| | - Arifullah Mohammed
- Department of Agriculture Science, Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, 17600, Jeli, Kelantan, Malaysia
- College of Agriculture, KL University, Vaddeswaram Campus, Guntur, Andhra Pradesh, 522302, India
| | - Kuttiappan Anitha
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, 474005, Madhya Pradesh, India
| | - Poojith Nuthalapati
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ganji Seeta Rama Raju
- Department of Energy and Materials Engineering, Dongguk University-Seoul, Seoul, 04620, Republic of Korea
| | - Yun Suk Huh
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon, 22212, Republic of Korea.
| | - Lvks Bhaskar
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, 495009, India.
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Ding K, Bao Q, He J, Wang J, Wang H. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway. Open Med (Wars) 2025; 20:20241059. [PMID: 40109328 PMCID: PMC11920760 DOI: 10.1515/med-2024-1059] [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: 05/10/2024] [Revised: 08/27/2024] [Accepted: 09/17/2024] [Indexed: 03/22/2025] Open
Abstract
Background Tetrahydropalmatine (THP) regulates mitochondrial function in vascular smooth muscle cells (VSMCs) to prevent or alleviate atherosclerosis (AS), with unclear specific mechanism. Methods AS models were constructed by oxidized low-density lipoprotein (ox-LDL)-treated VSMCs. Cell counting kit-8 for cell viability, wound scratch assay for cell migration, and flow cytometry for cell cycle, intracellular reactive oxygen species, and mitochondrial membrane potential (MMP) were performed. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels by biochemical kits, oxygen consumption rate (OCR) by seahorse apparatus, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay (TUNEL) staining, and apoptosis-related expression by western blot were detected. Ras homolog gene family A/Rho-associated protein kinase-1 (RhoA/ROCK1) levels were measured by western blot and ELISA. The RhoA agonist, U46619, was employed to validate mechanism of THP. Results THP suppressed cell cycle progression and cell migration whereas alleviating cell viability and oxidative stress, as reduced MDA and enhanced SOD levels in ox-LDL-incubated VSMCs. THP protected mitochondrial function by higher MMP levels and OCR values. Additionally, THP decreased TUNEL-positive cells, Bax, Caspase-3, RhoA, ROCK1, and osteopontin expression, while increased Bcl-2 and smooth muscle myosin heavy chain levels. Furthermore, U46619 intervention antagonized effects of THP. Conclusion THP improved mitochondrial function in VSMCs of AS by inhibiting RhoA/ROCK1 signaling pathway.
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Affiliation(s)
- Ke Ding
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, No. 54, Youdian Road, Hangzhou, 310006, Zhejiang, China
| | - Qiying Bao
- Department of Pharmacy, Hangzhou Fuyang Hospital of TCM Orthopedics, Hangzhou, 311499, Zhejiang, China
| | - Jiaqi He
- Traditional Chinese Medicine Dispensary, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, Zhejiang, China
| | - Jiahong Wang
- Traditional Chinese Medicine Dispensary, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, Zhejiang, China
| | - Hui Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548, Binwen Road, Hangzhou, 310053, Zhejiang, China
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Balde A, Benjakul S, Nazeer RA. A review on NLRP3 inflammasome modulation by animal venom proteins/peptides: mechanisms and therapeutic insights. Inflammopharmacology 2025; 33:1013-1031. [PMID: 39934538 DOI: 10.1007/s10787-025-01656-7] [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: 12/06/2024] [Accepted: 01/07/2025] [Indexed: 02/13/2025]
Abstract
The venom peptides from terrestrial as well as aquatic species have demonstrated potential in regulating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a sophisticated assemblage present in immune cells responsible for detecting and responding to external mediators. The NLRP3 inflammasome plays a role in several pathological conditions such as type 2 diabetes, hyperglycemia, Alzheimer's disease, obesity, autoimmune disorders, and cardiovascular disorders. Venom peptides derived from animal venoms have been discovered to selectively induce certain signalling pathways, such as the NLRP3 inflammasome, mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Experimental evidence has demonstrated that venom peptides can regulate the expression and activation of the NLRP3 inflammasome, resulting in the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Furthermore, these peptides have been discovered to impede the activation of the NLRP3 inflammasome, therefore diminishing inflammation and tissue injury. The functional properties of venom proteins and peptides obtained from snakes, bees, wasps, and scorpions have been thoroughly investigated, specifically targeting the NLRP3 inflammasome pathway, venom proteins and peptides have shown promise as therapeutic agents for the treatment of certain inflammatory disorders. This review discusses the pathophysiology of NLRP3 inflammasome in the onset of various diseases, role of venom as therapeutics. Further, various venom components and their role in the modulation of NLRP3 inflammasome are discoursed. A substantial number of venomous animals and their toxins are yet unexplored, and to comprehensively grasp the mechanisms of action of them and their potential as therapeutic agents, additional research is required which can lead to the development of novel therapeutics.
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Affiliation(s)
- Akshad Balde
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603 203, India
| | - Soottawat Benjakul
- International Center of Excellence in Seafood Science and Innovation, Faculty of Agro Industry, Prince of Songkla University, Hat Yai, 90110, Songkhla, Thailand
- Department of Food and Nutrition, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Rasool Abdul Nazeer
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603 203, India.
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Gao P, Yuan S, Wang Y, Wang Y, Li X, Liu T, Zheng Y, Wang J, Liu D, Xu L, Jiang Y, Zeng K, Tu P. Corydalis decumbens and tetrahydropalmatrubin inhibit macrophages inflammation to relieve rheumatoid arthritis by targeting Fosl2. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119348. [PMID: 39805480 DOI: 10.1016/j.jep.2025.119348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/05/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Corydalisdecumbens (Thunb.) (CD) is a traditional Chinese medicine and as a single herb or formula has been used to treat RA for decades. Rheumatoid arthritis (RA) is a persistent, systemic autoimmune inflammatory disease. However, the anti-inflammatory target, effective constituents and mechanism was unclear. AIM OF THE STUDY The purpose of this study was to identify anti-RA and anti-inflammatory targets of CD, elucidate effective constituents and molecular pharmacological mechanism. MATERIALS AND METHODS Anti-RA and anti-inflammatory effect of CD were evaluated on CIA-rats and in LPS-induced RAW264.7 cells respectively. The anti-inflammatory target of CD was identified using thermal proteome profiling (TPP). The recombinant Fosl2 protein was expressed and purified and the target-based effective constituents was screened with bio-layer interferometry (BLI) analysis. Combining photoaffinity probe, LC-MS/MS analysis, docking and point mutation, the binding site was confirmed between Fosl2 and THP. Furtherly, immunofluorescence (IF), co-immunoprecipitation (co-IP) were used to research the pharmacological mechanism of THP and the THP-influenced downstream pathways were elucidated by transcriptomics analysis. RESULTS CD had therapeutic effect on CIA-rats and a significant anti-inflammation on macrophages. Fosl2 was identified as a target of CD and we elucidated the target-based effective constituents was protoberberine-type alkaloids. THP can inhibit inflammation and transcription of AP-1 via targeting Fosl2 on LPS-induced RAW264.7 cells. For mechanism, THP promoted Fosl2 nuclear translocating and interacting with c-Jun. CONCLUSIONS These findings firstly elucidated the target and effective constituents of CD treating RA, and found that "undruggable target" Fosl2 can be used as therapeutic targets for RA. Meanwhile, our research suggested that THP has a significant potential for the treatment of RA.
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Affiliation(s)
- Peng Gao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Shuo Yuan
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yanhang Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yuqi Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xiaoshuang Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Tingting Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yongzhe Zheng
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Jing Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Dan Liu
- Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing, 100191, China
| | - Luzheng Xu
- Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing, 100191, China
| | - Yong Jiang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Kewu Zeng
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Pengfei Tu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
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Jiang Y, Cao J, Li R, Yu J, Peng Y, Huang Q, Zuo W, Chen J. Tetrahydropalmatine ameliorates peripheral nerve regeneration by enhancing macrophage anti-inflammatory response. Int Immunopharmacol 2025; 147:114000. [PMID: 39765002 DOI: 10.1016/j.intimp.2024.114000] [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: 08/18/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/29/2025]
Abstract
BACKGROUND Peripheral nerve injury (PNI) is a common clinical problem that can result in partial or complete loss of sensory, motor, and autonomic functions. Tetrahydropalmatine (THP), a Corydalis yanhusuo-derived phytochemical alkaloid, possesses hypnotic, soothing, analgesic, and other effects, but little is known about the effect of THP on moderating peripheral nerve regeneration and its possible underlying mechanism of action. PURPOSE In this study, we aim to elucidate the protective function of THP on PNI and further reveal the underlying pharmacological mechanisms. METHODS PNI rats were in suit injection of THP solution at doses of 40 mg/kg for consecutive 3, 7, or 28 days, followed by harvesting the sciatic nerve tissues. The protective effect of THP on PNI was evaluated by electrophysiological test, transmission electron microscopy, immunofluorescence (IF), and western blotting (WB). Macrophage polarization, the expression of inflammatory-related genes and cytokines, and its upstream signaling pathways were detected by IF, WB, enzyme-linked immunosorbent assay (ELISA), mRNA-seq, and WB. In vitro, the Raw 264.7 cells were treated with lipopolysaccharide containing with/without THP. The degree of inflammatory activation and its potential pharmacological mechanism were measured by ELISA, qRT-PCR, IF staining, flow cytometry, and WB. Additionally, a pharmacological agonist or inhibitor was added to the cell medium to further identify the role of THP's potential pharmacological mechanism in regulating inflammatory response via IF and ELISA technology. RESULTS Using the sciatic nerve crush model, we found that THP significantly enhanced the rate of axonal growth and functional recovery, and altered macrophage subtype transformation from the M1/M0 phenotype into the M2 phenotype, inducing the secretion of large amounts of anti-inflammatory factors. Moreover, THP significantly increased the phosphorylation level of PI3K, AKT, GSK3β, and IκBa, and decreased the expression of TLR4 protein and NF-κB phosphorylation. Similarly, in vitro, THP also facilitated Raw 264.7 cell polarization to the M2 subtype under the condition of LPS stimulation. Meanwhile, the change of PI3K/AKT/GSK3β and TLR4/NF-κB signaling-related proteins in vitro was consistent with the results in vivo. Additionally, the THP-medicated anti-inflammatory effect on Raw 264.7 cells was partly eliminated when pharmacological intervention of these two signaling pathways. CONCLUSIONS THP has anti-inflammatory effects on facilitating M2-subtype macrophage polarization, which produces abundant anti-inflammatory cytokines to ameliorate peripheral nerve regeneration. Moreover, the potential mechanism of THP action may be intimately associated with activating the PI3K/AKT/GSK3β axis and inhibiting the TLR4/NF-κB pathway.
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Affiliation(s)
- Yongsheng Jiang
- Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang 315700, P.R. China
| | - Jianye Cao
- Wenzhou Medical University, Wenzhou 325035, China
| | - Rui Li
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional KeyTechnology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
| | - Jia Yu
- Hangzhou Institute for Food and Drug Control, China
| | - Yan Peng
- Hangzhou Institute for Food and Drug Control, China
| | - Qiong Huang
- Xiangshan Maternal and Child Health Care Family Planning Service Center, China
| | - Wei Zuo
- Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang 315700, P.R. China.
| | - Junyue Chen
- Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang 315700, P.R. China.
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Ma C, Jiang Y, Xiang Y, Li C, Xie X, Zhang Y, You Y, Xie L, Gong J, Sun Y, Tong S, Song Q, Chen J, Xiao W. Metabolic Reprogramming of Macrophages by Biomimetic Melatonin-Loaded Liposomes Effectively Attenuates Acute Gouty Arthritis in a Mouse Model. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410107. [PMID: 39717013 PMCID: PMC11831490 DOI: 10.1002/advs.202410107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 11/25/2024] [Indexed: 12/25/2024]
Abstract
Gouty arthritis is characterized by an acute inflammatory response triggered by monosodium urate (MSU) crystals deposited in the joints and periarticular tissues. Current treatments bring little effects owing to serious side effects, necessitating the exploration of new and safer therapeutic options. Macrophages play a critical role in the initiation, progression, and resolution of acute gout, with the cellular profiles closely linked to their activation and polarization. This suggests that metabolic regulation can be of significance in managing gouty inflammation. In this study, it is demonstrated that melatonin, a natural hormone, modulates the metabolic remodeling of inflammatory macrophages by shifting their metabolism from glycolysis to oxidative phosphorylation, further altering functions of the pathogenic macrophage. To improve melatonin delivery to the inflamed sites, macrophage membrane-coated melatonin-loaded liposomes (MLT-MLP) are developed. Benefiting from the inflammation-homing characteristic of macrophage membrane, such engineered liposomes effectively target the inflamed site and demonstrate potent anti-inflammatory effects, achieving an enhanced amelioration of acute gouty arthritis. In conclusion, this study proposes a novel strategy aimed at metabolic reprogramming of macrophages to attenuate the pathological injuries in acute gout, providing a potential therapeutic strategy of gout-associated diseases, especially gouty arthritis.
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Affiliation(s)
- Chuchu Ma
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Yuyu Jiang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Yan Xiang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Chang Li
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Xiaoying Xie
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Yunkai Zhang
- Naval Medical Center, Naval Medical University, Shanghai, 200433, China
| | - Yang You
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Laozhi Xie
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Jianing Gong
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Yinzhe Sun
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Shiqiang Tong
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Qingxiang Song
- Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jun Chen
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China
| | - Wenze Xiao
- Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
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Wu D, Yang S, Yuan C, Zhang K, Tan J, Guan K, Zeng H, Huang C. Targeting purine metabolism-related enzymes for therapeutic intervention: A review from molecular mechanism to therapeutic breakthrough. Int J Biol Macromol 2024; 282:136828. [PMID: 39447802 DOI: 10.1016/j.ijbiomac.2024.136828] [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: 04/23/2024] [Revised: 10/02/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024]
Abstract
Purines are ancient metabolites with established and emerging metabolic and non-metabolic signaling attributes. The expression of purine metabolism-related genes is frequently activated in human malignancies, correlating with increased cancer aggressiveness and chemoresistance. Importantly, under certain stimulating conditions, the purine biosynthetic enzymes can assemble into a metabolon called "purinosomes" to enhance purine flux. Current evidence suggests that purine flux is regulated by a complex circuit that encompasses transcriptional, post-translational, metabolic, and association-dependent regulatory mechanisms. Furthermore, purines within the tumor microenvironment modulate cancer immunity through signaling mediated by purinergic receptors. The deregulation of purine metabolism has significant metabolic consequences, particularly hyperuricemia. Herbal-based therapeutics have emerged as valuable pharmacological interventions for the treatment of hyperuricemia by inhibiting the activity of hepatic XOD, modulating the expression of renal urate transporters, and suppressing inflammatory responses. This review summarizes recent advancements in the understanding of purine metabolism in clinically relevant malignancies and metabolic disorders. Additionally, we discuss the role of herbal interventions and the interaction between the host and gut microbiota in the regulation of purine homeostasis. This information will fuel the innovation of therapeutic strategies that target the disease-associated rewiring of purine metabolism for therapeutic applications.
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Affiliation(s)
- Di Wu
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China
| | - Shengqiang Yang
- School of Basic Medicine, Youjiang Medical University for Nationalities, Baise 533000, China
| | - Chenyang Yuan
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China
| | - Kejia Zhang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China
| | - Jiachen Tan
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China
| | - Kaifeng Guan
- School of Advanced Agricultural Sciences, Peking University, Beijing 100871, China.
| | - Hong Zeng
- School of Basic Medicine, Youjiang Medical University for Nationalities, Baise 533000, China.
| | - Chunjie Huang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
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Cao G, Zhu Z, Yang D, Wu W, Yang F, Liu Y, Xu J, Zhang Y. Fu'cupping Physical Permeation-Enhancing Technique Enhances the Therapeutic Efficacy of Corydalis yanhusuo Gel Plaster. PLANTA MEDICA 2024; 90:876-884. [PMID: 38876472 DOI: 10.1055/a-2344-8841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2024]
Abstract
Corydalis yanhusuo, a traditional Chinese medicine, is widely used to treat various pains, and its active ingredients are alkaloids. This study aimed to develop a new type of transdermal gel plaster containing the extract of C. yanhusuo. Studies have shown that Fu'cupping physical permeation-enhancing technique can promote the penetration of alkaloids and improve the efficacy of drugs. A transdermal gel plaster containing the extract of C. yanhusuo was prepared and optimized using an orthogonal experimental design. The skin permeation ability of the gel plaster was studied in vitro, while the anti-inflammatory and analgesic effects of the prepared patch alone or with Fu'cupping physical permeation-enhancing technique were evaluated in a rat model. The formulation of a gel plaster containing C. yanhusuo extract was successfully prepared with an optimized composition consisting of glycerin (15 g), sodium polyacrylate (2 g), silicon dioxide (0.3 g), ethanol (2 g), aluminum oxide (0.1 g), citric acid (0.05 g), the C. yanhusuo extract (3 g), and water (15 g). The cumulative transdermal permeation of dehydrocorydaline, corypalmine, tetrahydropalmatine, and corydaline in 24 h was estimated to be 569.7 ± 63.2, 74.5 ± 13.7, 82.4 ± 17.2, and 38.9 ± 8.1 µg/cm2, respectively. The in vitro diffusion of dehydrocorydaline and corydaline followed the zero-order kinetics profile, while that of corypalmine and tetrahydropalmatine followed a Higuchi equation. The prepared gel plaster significantly reduced paw swelling, downregulated inflammatory cytokines, and mitigated pain induced by mechanical or chemical stimuli. The Fu'cupping physical permeation-enhancing technique further improved the anti-inflammatory and analgesic effects of the patch. The combined application of the Fu'cupping physical permeation-enhancing technique and the alkaloid gel plaster may be effective against inflammation and pain.
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Affiliation(s)
- Guoqiong Cao
- College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- National Engineering Technology Research Center for Miao Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Zilan Zhu
- UCL School of Pharmacy, University College London, London, UK
| | - Dingyi Yang
- Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Wenyu Wu
- Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Fangfang Yang
- College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- National Engineering Technology Research Center for Miao Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yao Liu
- College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- National Engineering Technology Research Center for Miao Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jian Xu
- College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- National Engineering Technology Research Center for Miao Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yongping Zhang
- College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- National Engineering Technology Research Center for Miao Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
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Wu Y, Zhang Y, Wang Z, Lu Y, Wang Y, Pan J, Liu C, Zhu W, Wang Y. Bitongqing Attenuates CIA Rats by Suppressing Macrophage Pyroptosis and Modulating the NLRP3/Caspase-1/GSDMD Pathway. J Inflamm Res 2024; 17:5453-5469. [PMID: 39165322 PMCID: PMC11335010 DOI: 10.2147/jir.s466624] [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: 04/04/2024] [Accepted: 08/02/2024] [Indexed: 08/22/2024] Open
Abstract
Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and inflammatory cell infiltration. The traditional Chinese medicine prescription, Bitongqing (BTQ) exhibited significant efficacy in the clinical treatment of RA. However, the potential therapeutic mechanisms of BTQ in treating RA have not been fully investigated. This study aims to elucidate the effect of BTQ on collagen-induced arthritis (CIA) rat macrophage pyroptosis, providing a theoretical basis for treating RA. Methods This research employed liquid chromatography-mass spectrometry (LC-MS) to identify the primary components of BTQ. The therapeutic effects of BTQ were evaluated in a rat model of CIA. In vivo experiments were conducted using pathohistological staining, immunofluorescence, micro-CT, and Western blotting. Next, Mouse leukemia cells of monocyte macrophage cells (RAW264.7) were induced to undergo pyroptosis using lipopolysaccharide (LPS) and adenosine triphosphate (ATP), and the impact of BTQ on RAW264.7 macrophages was assessed through cell viability, immunofluorescence analysis, lactate dehydrogenase (LDH) secretion measurement, and Western blotting. Results BTQ had a therapeutic effect on CIA rats, which was mainly manifested as a reduction in joint inflammation, foot swelling, bone erosion, and amelioration of pathological changes in these rats. Further studies revealed that BTQ inhibited the levels of cytokine production interleukin-18 (IL-18) and interleukin-1β (IL-1β), and likewise, it inhibited the expression of key proteins in the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) mediated pyroptosis in the synovial tissues of CIA rats. The results of in vitro experiments demonstrated that BTQ attenuated LDH secretion, decreased IL-18 and IL-1β cytokine production, and downregulated expression of key proteins involved in the NLRP3-mediated pyroptosis on RAW264.7 macrophages. Conclusion The therapeutic potential of BTQ in CIA lies in its ability to inhibit NLRP3-mediated macrophage pyroptosis, thereby suggesting a promising strategy for the treatment of RA.
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Affiliation(s)
- Yunxia Wu
- Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Yue Zhang
- Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Zishan Wang
- Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Yun Lu
- Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Yabei Wang
- Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Jie Pan
- Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Chenxi Liu
- Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Wen Zhu
- Department of Rheumatology & Immunology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Yue Wang
- Department of Rheumatology & Immunology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
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11
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Ma S, Wei T, Zhang B, Zhang Y, Lai J, Qu J, Liu J, Yin P, Shang D. Integrated pharmacokinetic properties and tissue distribution of multiple active constituents in Qing-Yi Recipe: A comparison between granules and decoction. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155645. [PMID: 38643714 DOI: 10.1016/j.phymed.2024.155645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 04/06/2024] [Accepted: 04/14/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND Qing-Yi Recipe, a classic traditional Chinese medicine (TCM), is widely used for treating acute diseases of the abdomen, especially pancreatitis, the efficacy of which has been demonstrated in more than thirty clinical trials. However, the in-vivo pharmacodynamic material basis for this formula remains unclear. METHODS A sensitive and accurate method for quantifying twenty-two potential bioactive constituents of Qing-Yi Recipe in biological samples was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and this method was fully validated. Then, the integrated pharmacokinetic properties of Qing-Yi Recipe and its major metabolites in rats were investigated using the post-listed granules at both dosages. Subsequently, tissue distributions of those constituents in nine organs (especially the pancreas) were determined, and the overall parameters between the two formulations were compared. RESULTS Though the chemical profiles of the formulas varied across formulations, the overall exposure level was very similar, and baicalin, wogonoside, geniposide, rhein, costunolide, and paeoniflorin were the top six bioactive compounds in the circulation. All twenty-two natural products reached their first peak within 2 h, and several of them exhibited bimodal or multimodal patterns under the complicated transformation of metabolic enzymes, and the parameters of these products markedly changed compared with those of monomers. Diverse metabolites of emodin and baicalin/baicalein were detected in circulation and tissues, augmenting the in vivo forms of these compounds. Finally, the enrichment of tetrahydropalmatine and corydaline in the pancreas were observed and most compounds remained in the gastrointestinal system, providing a foundation basis for their potential regulatory effects on the gut microbiota as well as the intestinal functions. CONCLUSION Herein, the pharmacokinetic properties and tissue distribution of multiple potential active constituents in Qing-Yi Recipe were investigated at two dosages, providing a pharmacodynamic material basis of Qing-Yi Recipe for the first time. This investigation is expected to provide a new perspective and reference for future studies on the physiological disposition and potential pharmacodynamic basis of traditional Chinese medicine to treat acute abdomen diseases.
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Affiliation(s)
- Shurong Ma
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China
| | - Tianfu Wei
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China
| | - Biao Zhang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China
| | - Yunshu Zhang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning 116000, PR China
| | - Jinwen Lai
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning 116000, PR China
| | - Jialin Qu
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China
| | - Jianjun Liu
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China
| | - Peiyuan Yin
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning 116000, PR China.
| | - Dong Shang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning 116000, PR China.
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Liu J, Lin C, Wu M, Wang Y, Chen S, Yang T, Xie C, Kong Y, Wu W, Wang J, Ma X, Teng C. Co-delivery of indomethacin and uricase as a new strategy for inflammatory diseases associated with high uric acid. Drug Deliv Transl Res 2024; 14:1820-1838. [PMID: 38127247 DOI: 10.1007/s13346-023-01487-5] [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] [Accepted: 11/27/2023] [Indexed: 12/23/2023]
Abstract
Uric acid is the final metabolite in humans. High level of uric acid chronically induces urate deposition, aggravates kidney damage, and concomitantly causes an increase in inflammatory factors. Alleviating acute inflammation and decreasing uric acid levels are the key points in the treatment of inflammatory diseases associated with high uric acid. However, a drug delivery system that combines anti-inflammatory and uric acid reduction functions at the same time remains a challenge to be settled. Here, we designed a nanocrystal-based co-delivery platform, IND Nplex, characterized by loading of indomethacin (IND) and uricase. Compared with free IND or uricase, IND Nplex possessed a better anti-inflammatory effect by restraining the release of inflammation-related factors in vitro. In addition, pharmacokinetic and biodistribution studies revealed that IND Nplex significantly prolonged the retention time in vivo and was more concentrated in the kidney. In acute gouty arthritis model rats, IND Nplex markedly relieved ankle joint swelling and mitigated synovial inflammation. In acute kidney injury model rats, IND Nplex indicated better biocompatibility and significant amelioration of renal fibrosis. Moreover, IND Nplex showed the effect of anti-inflammatory and improved renal function via determination of inflammatory factors and biochemical markers in the serum and kidney. In conclusion, these results indicate that IND Nplex exerts anti-inflammatory activity and uric acid-lowering effect and could become a promising candidate for the treatment of uric acid-related diseases.
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Affiliation(s)
- Jie Liu
- Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Chenshi Lin
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Man Wu
- Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China
| | - Yingjie Wang
- Center for Translational Imaging, Northeastern University, 360 Huntington Ave., Boston, MA, 02115, USA
| | - Shenyu Chen
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Taiwang Yang
- Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China
| | - Chenlu Xie
- Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China
| | - Yue Kong
- Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China
| | - Wenliang Wu
- Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China
| | - Jiaping Wang
- Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China
| | - Xiaonan Ma
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
- Public Experimental Platform, China Pharmaceutical University, Nanjing, 210009, China.
| | - Chao Teng
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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13
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Ma Z, Zeng P, Feng H, Ni L. Network pharmacology and molecular docking to explore the treatment potential and molecular mechanism of Si-Miao decoction against gouty arthritis. Medicine (Baltimore) 2024; 103:e38221. [PMID: 39259129 PMCID: PMC11142817 DOI: 10.1097/md.0000000000038221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 09/12/2024] Open
Abstract
Gouty arthritis (GA) is a common metabolic rheumatological disease. Si-Miao decoction has therapeutic effects on GA. In our study, we investigated the mechanism of Si-Miao decoction against GA using network pharmacology and molecular docking analytical methods. The Traditional Chinese Medicine Systems Pharmacology Database was used as the basis for screening the main targets and agents of the Si-Miao decoction, and the Genecards, OMIM, and Drugbank databases were used to screen GA-related targets. They were analyzed using Venn with the drug targets to obtain the intersection targets. We used Cytoscape 3.9.1 to draw the "Drugs-Compounds-Targets" network and the String database for creative protein-protein interaction networks of target genes and filtered core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to analyze the core targets. Molecular docking was performed using AutoDockTools to predict the binding capacity between nuclear targets and active components in the Si-Miao decoction. A total of 50 chemically active components containing 53 common targets of Si-Miao decoction anti-GA and 53 potential drug target proteins were identified. Core targets, namely, TNF, STAT3, SRC, PPARG, TLR4, PTGS2, MMP9, RELA, TGFB1, and SIRT1, were obtained through PPI network analysis. GO and KEGG analyses showed that the mechanism of anti-GA in Si-Miao decoction may proceed by regulating biological processes such as inflammatory factor levels, cell proliferation, apoptosis, and lipid and glucose metabolism, and modulating the NOD-like receptor signaling pathway, IL-17 signaling pathway, TNF signaling pathway, NF-kappa B signaling pathway, and Toll-like receptor signaling pathway. We further screened the core targets, including PTGS2, MMP9, and PPAGR, as receptor proteins based on their degree value and molecular docking with the main active compounds in Si-Miao decoction, and found that baicalein had high affinity. In conclusion, Si-Miao decoction, through anti-inflammatory, apoptosis-regulating, and anti-oxidative stress action mechanisms in the treatment of GA.
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Affiliation(s)
- Zebing Ma
- Orthopedics (Orthopedic Group), The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
- Hunan University of Chinese Medicine, Changsha, China
| | - Peng Zeng
- Orthopedics (Orthopedic Group), The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Haibo Feng
- Orthopedics (Orthopedic Group), The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Lili Ni
- Orthopedics (Orthopedic Group), The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
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14
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Yang J, Deng J, Wang K, Wang A, Chen G, Chen Q, Ye M, Wu X, Wang X, Lin D. Tetrahydropalmatine promotes random skin flap survival in rats via the PI3K/AKT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 324:117808. [PMID: 38280663 DOI: 10.1016/j.jep.2024.117808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/13/2024] [Accepted: 01/19/2024] [Indexed: 01/29/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Flap necrosis is the most common complication after flap transplantation, but its prevention remains challenging. Tetrahydropalmatine (THP) is the main bioactive component of the traditional Chinese medicine Corydalis yanhusuo, with effects that include the activation of blood circulation, the promotion of qi, and pain relief. Although THP is widely used to treat various pain conditions, its impact on flap survival is unknown. AIM OF THE STUDY To explore the effect and mechanism of THP on skin flap survival. MATERIALS AND METHODS In this study, we established a modified McFarlane flap model, and the flap survival rate was calculated after 7 days of THP treatment. Angiogenesis and blood perfusion were evaluated using lead oxide/gelatin angiography and laser Doppler, respectively. Flap tissue obtained from zone II was evaluated histopathologically, by hematoxylin and eosin staining, and in assays for malondialdehyde content and superoxide dismutase activity. Immunofluorescence was performed to detect interleukin (IL)-6, tumor necrosis factor (TNF)-α, hypoxia-inducible factor (HIF)-1α, Bcl-2, Bax, caspase-3, caspase-9, SQSTM1/P62, Beclin-1, and LC3 expression, and Western blot to assess PI3K/AKT signaling pathway activation and Vascular endothelial growth factor (VEGF) expression. The role played by the autophagy pathway in flap necrosis was examined using rapamycin, a specific inhibitor of mTOR. RESULTS Experimentally, THP improved the survival rate of skin flaps, promoted angiogenesis, and improved blood perfusion. THP administration reduced the inflammatory response, oxidative stress, and apoptosis in addition to inhibiting autophagy via the PI3K/AKT/mTOR pathway. Rapamycin partially reversed these effects. CONCLUSION THP promotes skin flap survival via the PI3K/AKT signaling pathway.
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Affiliation(s)
- Jialong Yang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Jiapeng Deng
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Kaitao Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - An Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Guodong Chen
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Qingyu Chen
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Minle Ye
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Xinyu Wu
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, The First School of Clinical Medical, Wenzhou Medical, China
| | - Xinye Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Dingsheng Lin
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China.
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15
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Li L, Xu H, Wang Y, Zhang Y, Ye R, Li W, Yang J, Wu J, Li J, Jin E, Cao M, Li X, Li S, Liu C. From inflammation to pyroptosis: Understanding the consequences of cadmium exposure in chicken liver cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 272:116004. [PMID: 38290315 DOI: 10.1016/j.ecoenv.2024.116004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/13/2024] [Accepted: 01/19/2024] [Indexed: 02/01/2024]
Abstract
Hepatotoxicity is frequently observed following acute cadmium (Cd) exposure in chicken. Oxidative stress and subsequent inflammation are regarded as the main reasons for cadmium-induced liver injury. NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome-induced pyroptosis is involved in various inflammatory diseases, including liver injury. Poultry are more susceptible to harmful effects of heavy metals. However, the mechanism of cadmium-induced liver injury in chicken is still elusive. In this study, the effect of cadmium on chicken liver cells and the underlying mechanisms were investigated. The results showed mitochondria was damaged and excessive reactive oxygen species (ROS) were generated in chicken liver cell line LMH after cadmium exposure. Furthermore, cadmium-induced NLRP3 inflammasome activation and the cell membrane rupture indicated LMH cells pyroptosis. The ROS scavengers, acetylcysteine (NAC) and Mito-TEMPO prevented pyroptosis in LMH cells, suggesting that ROS were responsible for the activation of the NLRP3 inflammasome induced by cadmium. Additionally, anti-oxidative transcription factor Nrf2 was inhibited after cadmium exposure, explaining the excessive ROS generation. In summary, our study showed that cadmium leads to ROS generation by inducing mitochondrial damage and inhibiting Nrf2 activity, which promotes NLRP3 inflammasome activation and eventually induces pyroptosis in LMH cells.
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Affiliation(s)
- Lei Li
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Fengyang 233100, China; Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang 233100, China
| | - Hao Xu
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Yan Wang
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Yu Zhang
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Ruiqi Ye
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Wen Li
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Jingyi Yang
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Jiale Wu
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Jing Li
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Fengyang 233100, China; Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang 233100, China
| | - Erhui Jin
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Fengyang 233100, China; Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang 233100, China
| | - Mixia Cao
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Fengyang 233100, China; Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang 233100, China
| | - Xiaojin Li
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Fengyang 233100, China; Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang 233100, China
| | - Shenghe Li
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Fengyang 233100, China; Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang 233100, China.
| | - Chang Liu
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Fengyang 233100, China; Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang 233100, China.
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16
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Qin DE, Liang W, Yu Y, Whelan EC, Yuan X, Wang ZL, Wu XW, Cao ZR, Hua SY, Yin L, Shi L, Liang T. Modified Simiaowan prevents and treats gouty arthritis via the Nrf2/NLRP3 inflammasome signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116906. [PMID: 37442492 DOI: 10.1016/j.jep.2023.116906] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/03/2023] [Accepted: 07/10/2023] [Indexed: 07/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Modified Simiaowan (MSM) is a six-herb formula that has been shown to be effective in gouty arthritis (GA) has been proven, but its regulatory mechanism has not been fully elucidated. AIM OF THE STUDY To investigate the therapeutic effects and mechanism of MSM on gouty arthritis. MATERIALS AND METHODS Mouse J774A.1 macrophages were induced with Lipopolysaccharide (LPS) and then stimulated with Adenosine 5'-triphosphate (ATP) or Nigericin (Nig.) in presence or absence of MSM. Expression of key indicators of pro-inflammatory cytokines and the NLRP3 inflammasome signaling pathway were investigated by western blot, ELISA and qRT-PCR. Fluorescence staining and flow cytometry were performed to detect intracellular reactive oxygen species (ROS) production. Another study, the anti-inflammatory and antioxidant activities of MSM were evaluated in rats with monosodium urate (MSU) -induced gouty arthritis using ELISA, hematoxylin-eosin staining (HE) staining, immunohistochemistry, and oxidative stress kits to measure relevant inflammatory markers and oxidative stress-related biomarkers. RESULTS ELISA and qRT-PCR results demonstrated that MSM effectively reduced the secretion and the mRNA expression levels of pro-inflammatory cytokines. Western blot results indicated that MSM can suppress the expression of NLRP3, an inflamasomes-related protein. In addition, MSM regulated the transition from M1 to M2 macrophages and upregulated the protein expression of Nrf2 and HO-1. The flow cytometry results and the fluorescence staining result were consistent with hypothesis that a large amount of ROS could be effectively cleared by MSM. However, the anti-inflammatory effect of MSM was attenuated after the use of ML385. In vivo experiments demonstrated that joint swelling was significantly attenuated and knee neutrophil infiltration was alleviated in rats given MSM. SOD and GSH-px levels were elevated significantly, while COX-2 and MDA levels decreased. The immunohistochemical results suggested that MSM could effectively inhibit the activation of the NLRP3 inflammasome and the regulation of macrophage polarization in rat synovial tissue, and remarkably enhance the expression of Nrf2 and HO-1. CONCLUSION MSM has potent anti-inflammatory and antioxidant effects on MSU-induced gouty arthritis. MSM alleviates GA through Nrf2/HO-1/ROS/NLRP3 signaling pathway.
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Affiliation(s)
- Dong-Er Qin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Wei Liang
- Department of Traditional Chinese Medicine, Air Force Hospital, Eastern Theater of the Chinese People's Liberation Army, Nanjing, 210002, Jiangsu, China.
| | - Yun Yu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Eoin Christopher Whelan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6303, USA.
| | - Xin Yuan
- Nanjing Hospital of Traditional Chinese Medicine, Nanjing, 210001, China.
| | - Zhang-Lian Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Xiao-Wei Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Zi-Rui Cao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Sheng-Yi Hua
- Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China.
| | - Lian Yin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Le Shi
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Tao Liang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Chen X, Fu K, Lai Y, Dong C, Chen Z, Huang Y, Li G, Jiang R, Wu H, Wang A, Huang S, Shen L, Gao W, Li S. Tetrahydropalmatine: Orchestrating survival - Regulating autophagy and apoptosis via the PI3K/AKT/mTOR pathway in perforator flaps. Biomed Pharmacother 2023; 169:115887. [PMID: 37984303 DOI: 10.1016/j.biopha.2023.115887] [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: 09/14/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Introduced in clinical practice in 1989, perforator flaps are vital for tissue defect repair, but they are challenged by distal necrosis. Tetrahydropalmatine (THP) from celandine is renowned for its anti-inflammatory and analgesic effects. This study investigates THP's use in perforator flaps. METHODS Thirty rats were divided into a control group and four THP concentration groups, while seventy-eight rats were categorized as control, THP, THP combined with rapamycin (RAP), and RAP alone. We created 11 cm by 2.5 cm multi-regional perforator flaps on rat backs, assessing survival blood flow and extracting skin flap tissue for autophagy, oxidative stress, apoptosis, and angiogenesis markers. RESULTS The THP group exhibited significantly reduced distal necrosis, increased blood flow density, and survival area on the seventh day compared to controls. Immunohistochemistry and Western blot results demonstrated improved anti-oxidative stress and angiogenesis markers, along with decreased autophagy and apoptosis indicators. Combining THP with RAP diminished flap survival compared to THP alone. This was supported by protein expression changes in the PI3K-AKT-mTOR pathway. CONCLUSION THP enhances flap survival by modulating autophagy, reducing tissue edema, promoting angiogenesis, and mitigating apoptosis and oxidative stress. THP offers a potential strategy for enhancing multi-regional perforator flap survival through the PI3K/AKT/mTOR pathway. These findings highlight THP's promise in combatting perforator flap necrosis, uncovering a novel mechanism for its impact on flap survival.
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Affiliation(s)
- Xuankuai Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Kejian Fu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Yingying Lai
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Chengji Dong
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Zhuliu Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Yingying Huang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Guangyao Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Renhao Jiang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Hongqiang Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Anyuan Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Shaojie Huang
- Wenzhou Medical University School of Laboratory Medicine and Life Sciences, China
| | - Liyan Shen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Weiyang Gao
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China
| | - Shi Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325027, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China.
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Yan Y, Yu L, Chen B, Cao C, Zhao H, Wang Q, Xie D, Xi Y, Zhang C, Cheng J. Mastoparan M Suppressed NLRP3 Inflammasome Activation by Inhibiting MAPK/NF-κB and Oxidative Stress in Gouty Arthritis. J Inflamm Res 2023; 16:6179-6193. [PMID: 38116368 PMCID: PMC10730329 DOI: 10.2147/jir.s434587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/28/2023] [Indexed: 12/21/2023] Open
Abstract
Background Gouty arthritis is characterized by the accumulation of monosodium urate crystals (MSU) in the synovial joints and surrounding tissues. Mastoparan M (Mast-M) is a biologically active peptide composed of 14 amino acids, extracted from wasp venom. This study aims to assess the impact of Mast-M on in vitro and in vivo gouty arthritis induced by lipolyaccharide (LPS) plus MSU crystal stimulation. Methods PMA-differentiated THP-1 macrophages were pre-treated with Mast-M or left untreated, followed by stimulation with LPS and MSU crystals. Cell lysates were collected to assess the expression of the NLRP3 inflammasome, inflammatory signaling pathways, and oxidative stress. Furthermore, to evaluate the in vivo anti-inflammatory effect of Mast-M, an experimental acute gouty arthritis mouse model was established through intra-articular injection of MSU crystals. Results Mast-M treatment demonstrated significant inhibition of the phosphorylation of MAPKs/NF-κB signaling pathways and reduction in oxidative stress expression in LPS and MSU-induced THP-1 macrophages. This resulted in the suppression of downstream NLRP3 inflammasome activation and IL-1β release. In vivo, Mast-M effectively attenuated the inflammation induced by MSU in mice with gouty arthritis. Specifically, Mast-M reduced swelling in the paws, inhibited the infiltration of neutrophils and macrophages into periarticular tissue, and decreased the activation of the NLRP3 inflammasome and IL-1β production. Conclusion Mast-M significantly improves gouty arthritis, and its potential mechanism may be achieved by inhibiting the MAPK/NF-κB pathway and alleviating oxidative stress, thus suppressing the activation of NLRP3 inflammasomes.
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Affiliation(s)
- Yunbo Yan
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Linqian Yu
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Binyang Chen
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Chang’an Cao
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Hairong Zhao
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, People’s Republic of China
| | - Qiang Wang
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - De Xie
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Yuemei Xi
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Chenggui Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, People’s Republic of China
| | - Jidong Cheng
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
- Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, People’s Republic of China
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Deng W, Wu L, Xiao Z, Li Y, Zheng Z, Chen S. Structural Characterization and Anti-Inflammatory Activity of Polysaccharides from Tremella fuciformis on Monosodium Urate-Stimulated RAW264.7 Macrophages. Foods 2023; 12:4398. [PMID: 38137202 PMCID: PMC10743196 DOI: 10.3390/foods12244398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/23/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
The structural characteristics and anti-inflammatory activity of Tremella fuciformis polysaccharides (TFPs) were investigated. The study showed that TFPs were mainly composed of mannose, rhamnose, glucuronic acid, glucose, galactose, xylose, and fucose. TFPs significantly inhibited monosodium urate (MSU)-induced inflammation of RAW264.7 cells, as well as the secretion levels of TNF-α, IL-1β, and IL-18 cytokines. The concentrations of malondialdehyde and reactive oxygen species in RAW264.7 macrophages were reduced, but superoxide dismutase activity was increased. RNA-Seq technology was applied to explore the mechanisms of TFPs ameliorating MSU-induced inflammation of RAW264.7 macrophages. Results revealed that TFPs significantly reduce MSU-stimulated inflammatory damage in RAW 264.7 cells by inhibiting signaling pathways like the hypoxia inducible factor-1 (HIF-1) signaling pathway and erythroblastic oncogene B (ErbB) signaling pathway. This study provides a foundation for TFPs to be developed as novel anti-inflammatory drugs.
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Affiliation(s)
- Wei Deng
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (W.D.); (Z.Z.)
| | - Li Wu
- Institute of Food Science and Technology, Fujian Academy of Agricultural Sciences, Fuzhou 350003, China; (L.W.); (Z.X.); (S.C.)
- National Research and Development Center of Edible Fungus Processing Technology, Fuzhou 350003, China
- Key Laboratory of Subtropical Characteristic Fruits, Vegetables and Edible Fungi Processing (Coconstruction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Fuzhou 350003, China
- Fujian Key Laboratory of Agricultural Product (Food) Processing, Fuzhou 350003, China
| | - Zheng Xiao
- Institute of Food Science and Technology, Fujian Academy of Agricultural Sciences, Fuzhou 350003, China; (L.W.); (Z.X.); (S.C.)
- National Research and Development Center of Edible Fungus Processing Technology, Fuzhou 350003, China
- Key Laboratory of Subtropical Characteristic Fruits, Vegetables and Edible Fungi Processing (Coconstruction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Fuzhou 350003, China
- Fujian Key Laboratory of Agricultural Product (Food) Processing, Fuzhou 350003, China
| | - Yibin Li
- Institute of Food Science and Technology, Fujian Academy of Agricultural Sciences, Fuzhou 350003, China; (L.W.); (Z.X.); (S.C.)
- National Research and Development Center of Edible Fungus Processing Technology, Fuzhou 350003, China
- Key Laboratory of Subtropical Characteristic Fruits, Vegetables and Edible Fungi Processing (Coconstruction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Fuzhou 350003, China
- Fujian Key Laboratory of Agricultural Product (Food) Processing, Fuzhou 350003, China
| | - Zhipeng Zheng
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (W.D.); (Z.Z.)
| | - Shouhui Chen
- Institute of Food Science and Technology, Fujian Academy of Agricultural Sciences, Fuzhou 350003, China; (L.W.); (Z.X.); (S.C.)
- National Research and Development Center of Edible Fungus Processing Technology, Fuzhou 350003, China
- Key Laboratory of Subtropical Characteristic Fruits, Vegetables and Edible Fungi Processing (Coconstruction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Fuzhou 350003, China
- Fujian Key Laboratory of Agricultural Product (Food) Processing, Fuzhou 350003, China
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Feng JH, Chen K, Shen SY, Luo YF, Liu XH, Chen X, Gao W, Tong YR. The composition, pharmacological effects, related mechanisms and drug delivery of alkaloids from Corydalis yanhusuo. Biomed Pharmacother 2023; 167:115511. [PMID: 37729733 DOI: 10.1016/j.biopha.2023.115511] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 09/22/2023] Open
Abstract
Corydalis yanhusuo W. T. Wang, also known as yanhusuo, yuanhu, yanhu and xuanhu, is one of the herb components of many Chinese Traditional Medicine prescriptions such as Jin Ling Zi San and Yuanhu-Zhitong priscription. C. yanhusuo was traditionally used to relieve pain and motivate blood and Qi circulation. Now there has been growing interest in pharmacological effects of alkaloids, the main bioactive components of C. yanhusuo. Eighty-four alkaloids isolated from C. yanhusuo are its important bioactive components and can be characterized into protoberberine alkaloids, aporphine alkaloids, opiate alkaloids and others and proper extraction or co-administration methods modulate their contents and efficacy. Alkaloids from C. yanhusuo have various pharmacological effects on the nervous system, cardiovascular system, cancer and others through multiple molecular mechanisms such as modulating neurotransmitters, ion channels, gut microbiota, HPA axis and signaling pathways and are potential treatments for many diseases. Plenty of novel drug delivery methods such as autologous red blood cells, self-microemulsifying drug delivery systems, nanoparticles and others have also been investigated to better exert the effects of alkaloids from C. yanhusuo. This review summarized the alkaloid components of C. yanhusuo, their pharmacological effects and mechanisms, and methods of drug delivery to lay a foundation for future investigations.
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Affiliation(s)
- Jia-Hua Feng
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Kang Chen
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Si-Yu Shen
- School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
| | - Yun-Feng Luo
- School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
| | - Xi-Hong Liu
- School of Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Xin Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Wei Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
| | - Yu-Ru Tong
- School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
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Wang Y, Xu Y, Tan J, Ye J, Cui W, Hou J, Liu P, Li J, Wang S, Zhao Q. Anti-inflammation is an important way that Qingre-Huazhuo-Jiangsuan recipe treats acute gouty arthritis. Front Pharmacol 2023; 14:1268641. [PMID: 37881185 PMCID: PMC10597652 DOI: 10.3389/fphar.2023.1268641] [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: 07/28/2023] [Accepted: 09/21/2023] [Indexed: 10/27/2023] Open
Abstract
Background: Acute gouty arthritis (AGA) significantly impairs patients' quality of life. Currently, existing therapeutic agents exhibit definite efficacy but also lead to serious adverse reactions. Therefore, it is essential to develop highly efficient therapeutic agents with minimal adverse reactions, especially within traditional Chinese medicine (TCM). Additionally, food polyphenols have shown potential in treating various inflammatory diseases. The Qingre-Huazhuo-Jiangsuan-Recipe (QHJR), a modification of Si-Miao-San (SMS), has emerged as a TCM remedy for AGA with no reported side effects. Recent research has also highlighted a strong genetic link to gout. Methods: The TCM System Pharmacology (TCMSP) database was used to collect the main chemical components of QHJR and AGA-related targets for predicting the metabolites in QHJR. HPLC-Q-Orbitrap-MS was employed to identify the ingredients of QHJR. The collected metabolites were then used to construct a Drugs-Targets Network in Cytoscape software, ranked based on their "Degree" of significance. Differentially expressed genes (DEGs) were screened in the Gene Expression Omnibus (GEO) database using GEO2R online analysis. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. The DEGs were utilized to construct a Protein-Protein Interaction (PPI) Network via the STRING database. In vivo experimental validation was conducted using colchicine, QHJR, rapamycin (RAPA), and 3-methyladenine (3-MA) as controls to observe QHJR's efficacy in AGA. Synovial tissues from rats were collected, and qRT-PCR and Western blot assays were employed to investigate Ampk-related factors (Ampk, mTOR, ULK1), autophagy-related factors (Atg5, Atg7, LC3, p62), and inflammatory-related factors (NLRP3). ELISA assays were performed to measure inflammatory-related factor levels (IL-6, IL-1β, TNF-α), and H&E staining was used to examine tissue histology. Results: Network analysis screened out a total of 94 metabolites in QHJR for AGA. HPLC-Q-Orbitrap-MS analysis identified 27 of these metabolites. Notably, five metabolites (Neochlorogenic acid, Caffeic acid, Berberine, Isoliquiritigenin, Formononetin) were not associated with any individual herbal component of QHJR in TCMSP database, while six metabolites (quercetin, luteolin, formononetin, naringenin, taxifolin, diosgenin) overlapped with the predicted results from the previous network analysis. Further network analysis highlighted key components, such as Caffeic acid, cis-resveratrol, Apigenin, and Isoliquiritigenin. Other studies have found that their treatment of AGA is achieved through reducing inflammation, consistent with this study, laying the foundation for the mechanism study of QHJR against AGA. PPI analysis identified TNF, IL-6, and IL-1β as hub genes. GO and KEGG analyses indicated that anti-inflammation was a key mechanism in AGA treatment. All methods demonstrated that inflammatory expression increased in the Model group but was reversed by QHJR. Additionally, autophagy-related expression increased following QHJR treatment. The study suggested that AMPKα and p-AMPKα1 proteins were insensitive to 3 MA and RAPA, implying that AMPK may not activate autophagy directly but through ULK1 and mTOR. Conclusion: In conclusion, this study confirms the effectiveness of QHJR, a modified formulation of SMS (a classic traditional Chinese medicine prescription for treating gout), against AGA. QHJR, as a TCM formula, offers advantages such as minimal safety concerns and potential long-term use. The study suggests that the mechanism by which QHJR treats AGA may involve the activation of the AMPK/mTOR/ULK1 pathway, thereby regulating autophagy levels, reducing inflammation, and alleviating AGA. These findings provide new therapeutic approaches and ideas for the clinical treatment of AGA.
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Affiliation(s)
- Yazhuo Wang
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yang Xu
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jingrui Tan
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiaxue Ye
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Weizhen Cui
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Hou
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Peiyu Liu
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jianwei Li
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shiyuan Wang
- Institute of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qingyang Zhao
- Institute of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, China
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22
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Mohapatra A, Mohanty A, Sathiyamoorthy P, Chahal S, Vijayan V, Rajendrakumar SK, Park IK. Targeted treatment of gouty arthritis by biomineralized metallic nanozyme-mediated oxidative stress-mitigating nanotherapy. J Mater Chem B 2023; 11:7684-7695. [PMID: 37464890 DOI: 10.1039/d3tb00669g] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
Gouty arthritis is characterized by chronic deposition of monosodium urate (MSU) crystals in the joints and other tissues, resulting in the production of excess reactive oxygen species (ROS) and proinflammatory cytokines that intensify synovial inflammation. This condition is mainly associated with inflammatory M1 macrophage activation and oxidative stress production. Hence, gout symptoms can often be resolved by eliminating M1 macrophage activation and scavenging oxidative stress in the inflamed areas. Herein, we developed M1-macrophage-targeting biomineralized metallic nanozymes (FALNZs) that deplete oxidative stress and reduce the M1 macrophage levels to mitigate gouty arthritis. Intra-articular injection of the FALNZs targets inflammatory macrophages and suppresses ROS levels in joints with MSU-crystal-induced arthritis. In addition, the FALNZs alleviate joint swelling, inflammatory cytokine production, and pathological features of the joints. Overall, the proposed therapeutic approach is biocompatible and is an effective ROS scavenger for the treatment of gouty pathogenesis.
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Affiliation(s)
- Adityanarayan Mohapatra
- Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, South Korea.
| | - Ayeskanta Mohanty
- Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, South Korea.
| | - Padmanaban Sathiyamoorthy
- Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, South Korea.
| | - Sahil Chahal
- Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, South Korea.
| | - Veena Vijayan
- Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, South Korea.
| | | | - In-Kyu Park
- Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, South Korea.
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23
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Liu W, Peng J, Wu Y, Ye Z, Zong Z, Wu R, Li H. Immune and inflammatory mechanisms and therapeutic targets of gout: An update. Int Immunopharmacol 2023; 121:110466. [PMID: 37311355 DOI: 10.1016/j.intimp.2023.110466] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/31/2023] [Accepted: 06/06/2023] [Indexed: 06/15/2023]
Abstract
Gout is an autoimmune disease characterized by acute or chronic inflammation and damage to bone joints induced due to the precipitation of monosodium urate (MSU) crystals. In recent years, with the continuous development of animal models and ongoing clinical investigations, more immune cells and inflammatory factors have been found to play roles in gouty inflammation. The inflammatory network involved in gout has been discovered, providing a new perspective from which to develop targeted therapy for gouty inflammation. Studies have shown that neutrophil macrophages and T lymphocytes play important roles in the pathogenesis and resolution of gout, and some inflammatory cytokines, such as those in the interleukin-1 (IL-1) family, have been shown to play anti-inflammatory or proinflammatory roles in gouty inflammation, but the mechanisms underlying their roles are unclear. In this review, we explore the roles of inflammatory cytokines, inflammasomes and immune cells in the course of gout development and the research status of therapeutic drugs used for inflammation to provide insights into future targeted therapy for gouty inflammation and the direction of gout pathogenesis research.
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Affiliation(s)
- Wenji Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, 330006 Nanchang, China; The Second Clinical Medical College of Nanchang University, 330006 Nanchang, China
| | - Jie Peng
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, 330006 Nanchang, China; The Second Clinical Medical College of Nanchang University, 330006 Nanchang, China
| | - Yixin Wu
- Queen Mary College of Nanchang University, 330006 Nanchang, China
| | - Zuxiang Ye
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, 330006 Nanchang, China; The Second Clinical Medical College of Nanchang University, 330006 Nanchang, China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, 1 MinDe Road, 330006 Nanchang, China
| | - Rui Wu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, 330006 Nanchang, China.
| | - Hui Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, 330006 Nanchang, China.
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Cui YR, Bu ZQ, Yu HY, Yan LL, Feng J. Emodin attenuates inflammation and demyelination in experimental autoimmune encephalomyelitis. Neural Regen Res 2023; 18:1535-1541. [PMID: 36571359 PMCID: PMC10075100 DOI: 10.4103/1673-5374.358612] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Emodin, a substance extracted from herbs such as rhubarb, has a protective effect on the central nervous system. However, the potential therapeutic effect of emodin in the context of multiple sclerosis remains unknown. In this study, a rat model of experimental autoimmune encephalomyelitis was established by immune induction to simulate multiple sclerosis, and the rats were intraperitoneally injected with emodin (20 mg/kg/d) from the day of immune induction until they were sacrificed. In this model, the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the microglia exacerbated neuroinflammation, playing an important role in the development of multiple sclerosis. In addition, silent information regulator of transcription 1 (SIRT1)/peroxisome proliferator-activated receptor-alpha coactivator (PGC-1α) was found to inhibit activation of the NLRP3 inflammasome, and SIRT1 activation reduced disease severity in experimental autoimmune encephalomyelitis. Furthermore, treatment with emodin decreased body weight loss and neurobehavioral deficits, alleviated inflammatory cell infiltration and demyelination, reduced the expression of inflammatory cytokines, inhibited microglial aggregation and activation, decreased the levels of NLRP3 signaling pathway molecules, and increased the expression of SIRT1 and PGC-1α. These findings suggest that emodin improves the symptoms of experimental autoimmune encephalomyelitis, possibly through regulating the SIRT1/PGC-1α/NLRP3 signaling pathway and inhibiting microglial inflammation. These findings provide experimental evidence for treatment of multiple sclerosis with emodin, enlarging the scope of clinical application for emodin.
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Affiliation(s)
- Yue-Ran Cui
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zhong-Qi Bu
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Hai-Yang Yu
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Li-Li Yan
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Juan Feng
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
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Charoenwutthikun S, Chanjitwiriya K, Roytrakul S, Kunthalert D. A wild rice-derived peptide R14 ameliorates monosodium urate crystals-induced IL-1β secretion through inhibition of NF-κB signaling and NLRP3 inflammasome activation. PeerJ 2023; 11:e15295. [PMID: 37197585 PMCID: PMC10184658 DOI: 10.7717/peerj.15295] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 04/04/2023] [Indexed: 05/19/2023] Open
Abstract
Gout is an inflammatory arthritis initiated by the deposition of monosodium urate crystals (MSU) around the joints and surrounding tissues. MSU crystals activate the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome to the release of interleukin-1β (IL-1β). Gout can have a substantial impact on patient's quality of life, and currently available medicines are unable to meet all the clinical needs. This study explored anti-gout potentials of the Rice14 (R14) peptide, a peptide derived from leaves of wild rice Oryza minuta. The effects of R14 peptide on IL-1β secretion in THP-1 macrophages with MSU crystals-induced inflammation were examined. Our results clearly showed that the R14 peptide significantly inhibited the secretion of IL-1β in MSU crystals-induced macrophages, and the effects were dose-related. For safety testing, the R14 peptide did not show both cytotoxicity and hemolytic activity. In addition, the R14 peptide strongly suppressed the phospho-IκB-α and nuclear factor kappa-B (NF-κB) p65 proteins in NF-κB signaling pathway, reduced the NLRP3 expression and inhibited the MSU crystals-mediated cleavage of caspase-1 as well as mature IL-1β. The R14 peptide also reduced MSU-triggered intracellular ROS levels in macrophages. Taken together, these results indicated that R14 peptide inhibited MSU crystals-induced IL-1β production through NF-κB and NLRP3 inflammasome activation. Our findings demonstrated that R14 peptide, the newly recognized peptide from wild rice, possessed potent regulatory activity against IL-1β production in MSU crystals-induced inflammation, and we therefore propose that the R14 peptide is a promising molecule with potential clinical application in the treatment of MSU crystals-induced inflammation.
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Affiliation(s)
- Supattra Charoenwutthikun
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Kasem Chanjitwiriya
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Sittiruk Roytrakul
- National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Thailand Science Park, Pathumthani, Thailand
| | - Duangkamol Kunthalert
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
- Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
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Blocking SphK/S1P/S1PR1 axis signaling pathway alleviates remifentanil-induced hyperalgesia in rats. Neurosci Lett 2023; 801:137131. [PMID: 36801239 DOI: 10.1016/j.neulet.2023.137131] [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: 11/03/2022] [Revised: 01/28/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023]
Abstract
Recent research shows a correlation between altered sphingolipid metabolism and nociceptive processing. Activation of the sphingosine-1-phosphate receptor 1 subtype (S1PR1) by its ligand, sphingosine-1-phosphate (S1P), causes neuropathic pain. However, its role in remifentanil-induced hyperalgesia (RIH) has not been investigated. The purpose of this research was to establish if the SphK/S1P/S1PR1 axis mediated remifentanil-induced hyperalgesia and identify its potential targets. This study examined the protein expression of ceramide, sphingosine kinases (SphK), S1P, and S1PR1 in the spinal cord of rats treated with remifentanil (1.0 μg/kg/min for 60 min). Prior to receiving remifentanil, rats were injected with SK-1 (a SphK inhibitor); LT1002 (a S1P monoclonal antibody); CYM-5442, FTY720, and TASP0277308（the S1PR1 antagonists); CYM-5478 (a S1PR2 agonist); CAY10444 (a S1PR3 antagonist); Ac-YVAD-CMK (a caspase-1 antagonist); MCC950 (the NOD-like receptor protein 3 (NLRP3) inflammasome antagonist); and N-tert-Butyl-α-phenylnitrone (PBN, a reactive oxygen species (ROS) scavenger). Mechanical and thermal hyperalgesia were evaluated at baseline (24 h prior to remifentanil infusion) and 2, 6, 12, and 24 h following remifentanil administration. The expression of the NLRP3-related protein (NLRP3, caspase-1), pro-inflammatory cytokines (interleukin-1β(IL-1β), IL-18), and ROS was found in the spinal dorsal horns. In the meantime, immunofluorescence was used to ascertain if S1PR1 co-localizes with astrocytes. Remifentanil infusion induced considerable hyperalgesia in addition to increased ceramide, SphK, S1P, and S1PR1, NLRP3-related protein (NLRP3, Caspase-1, IL-1β, IL-18) and ROS expression, and S1PR1 localized astrocytes. By blocking the SphK/S1P/S1PR1 axis, remifentanil-induced hyperalgesia was reduced, as was the expression of NLRP3, caspase-1, pro-inflammatory cytokines (IL-1β, IL-18) and ROS in the spinal cord. In addition, we observed that suppressing NLRP3 or ROS signal attenuated the mechanical and thermal hyperalgesia induced by remifentanil. Our findings indicate that the SphK/SIP/S1PR1 axis regulates the expression of NLRP3, Caspase-1, IL-1β, IL-18 and ROS in the spinal dorsal horn to mediate remifentanil-induced hyperalgesia. These findings may contribute to pain and SphK/S1P/S1PR1 axis research positively, and inform the future study of this commonly used analgesic.
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Liu YR, Wang JQ, Li J. Role of NLRP3 in the pathogenesis and treatment of gout arthritis. Front Immunol 2023; 14:1137822. [PMID: 37051231 PMCID: PMC10083392 DOI: 10.3389/fimmu.2023.1137822] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/14/2023] [Indexed: 03/29/2023] Open
Abstract
Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.
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Affiliation(s)
- Ya-ru Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- The Grade 3 Pharmaceutical Chemistry Laboratory, State Administration of Traditional Chinese Medicine, Hefei, China
- *Correspondence: Ya-ru Liu, ; Jun Li,
| | - Jie-quan Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
| | - Jun Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- *Correspondence: Ya-ru Liu, ; Jun Li,
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High-Throughput Sequencing Reveals That Rotundine Inhibits Colorectal Cancer by Regulating Prognosis-Related Genes. J Pers Med 2023; 13:jpm13030550. [PMID: 36983731 PMCID: PMC10052610 DOI: 10.3390/jpm13030550] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 03/22/2023] Open
Abstract
Background: Rotundine is an herbal medicine with anti-cancer effects. However, little is known about the anti-cancer effect of rotundine on colorectal cancer. Therefore, our study aimed to investigate the specific molecular mechanism of rotundine inhibition of colorectal cancer. Methods: MTT and cell scratch assay were performed to investigate the effects of rotundine on the viability, migration, and invasion ability of SW480 cells. Changes in cell apoptosis were analyzed by flow cytometry. DEGs were detected by high-throughput sequencing after the action of rotundine on SW480 cells, and the DEGs were subjected to function enrichment analysis. Bioinformatics analyses were performed to screen out prognosis-related DEGs of COAD. Followed by enrichment analysis of prognosis-related DEGs. Furthermore, prognostic models were constructed, including ROC analysis, risk curve analysis, PCA and t-SNE, Nomo analysis, and Kaplan–Meier prognostic analysis. Results: In this study, we showed that rotundine concentrations of 50 μM, 100 μM, 150 μM, and 200 μM inhibited the proliferation, migration, and invasion of SW480 cells in a time- and concentration-dependent manner. Rotundine does not induce SW480 cell apoptosis. Compared to the control group, high-throughput results showed that there were 385 DEGs in the SW480 group. And DEGs were associated with the Hippo signaling pathway. In addition, 16 of the DEGs were significantly associated with poorer prognosis in COAD, with MEF2B, CCDC187, PSD2, RGS16, PLXDC1, HELB, ASIC3, PLCH2, IGF2BP3, CLHC1, DNHD1, SACS, H1-4, ANKRD36, and ZNF117 being highly expressed in COAD and ARV1 being lowly expressed. Prognosis-related DEGs were mainly enriched in cancer-related pathways and biological functions, such as inositol phosphate metabolism, enterobactin transmembrane transporter activity, and enterobactin transport. Prognostic modeling also showed that these 16 DEGs could be used as predictors of overall survival prognosis in COAD patients. Conclusions: Rotundine inhibits the development and progression of colorectal cancer by regulating the expression of these prognosis-related genes. Our findings could further provide new directions for the treatment of colorectal cancer.
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Huang Z, Zhang W, An Q, Lang Y, Liu Y, Fan H, Chen H. Exploration of the anti-hyperuricemia effect of TongFengTangSan (TFTS) by UPLC-Q-TOF/MS-based non-targeted metabonomics. Chin Med 2023; 18:17. [PMID: 36797795 PMCID: PMC9933412 DOI: 10.1186/s13020-023-00716-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 01/28/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND TongFengTangSan (TFTS) is a commonly used Tibetan prescription for gout treatment. Previously, TFTS (CF) was confirmed to have a significant uric acid-lowering effect. However, the anti-hyperuricemia mechanisms and the main active fractions remain unclear. The current study aimed to investigate the anti-hyperuricemia mechanism using metabolomics and confirm the active CF fraction. METHODS The hyperuricemia model was established through intraperitoneal injection containing 100 mg/kg potassium oxonate and 150 mg/kg hypoxanthine by gavage. We used serum uric acid (sUA), creatinine (CRE), blood urea nitrogen (BUN), xanthine oxidase (XOD) activity, interleukin-6 (IL-6) and interleukin-1β (IL-1β) as indicators to evaluate the efficacy of CF and the four fractions (SX, CF30, CF60, and CF90). The anti-hyperuricemia mechanism of CF was considered through non-targeted metabolomics depending on the UPLC-Q-TOF-MS technology. Principle component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) helped explore the potential biomarkers in hyperuricemia. Moreover, the differential metabolites and metabolic pathways regulated by CF and four fractions were also assessed. RESULTS CF revealed a significant anti-hyperuricemia effect by down-regulating the level of sUA, sCRE, sIL-1β, and XOD. SX, CF30, CF60, and CF90 differed in the anti-hyperuricemia effect. Only CF60 significantly lowered the sUA level among the four fractions, and it could be the main efficacy fraction of TFTS. Forty-three differential metabolites were identified in hyperuricemia rats from plasma and kidney. Pathway analysis demonstrated that seven pathways were disrupted among hyperuricemia rats. CF reversed 19 metabolites in hyperuricemia rats and exerted an anti-hyperuricemia effect by regulating purine metabolism. CF60 was the main active fraction of TFTS and exerted a similar effect of CF by regulating purine metabolism. CONCLUSIONS CF and CF60 could exert an anti-hyperuricemia effect by regulating the abnormal purine metabolism because of hyperuricemia while improving intestinal and renal function. CF60 could be the main active fraction of TFTS.
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Affiliation(s)
- Zhichao Huang
- grid.411868.20000 0004 1798 0690Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330004 China
| | - Wugang Zhang
- grid.411868.20000 0004 1798 0690Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330004 China ,grid.411868.20000 0004 1798 0690State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006 China
| | - Qiong An
- grid.411868.20000 0004 1798 0690Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330004 China
| | - Yifan Lang
- grid.411868.20000 0004 1798 0690State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006 China
| | - Ye Liu
- grid.411868.20000 0004 1798 0690State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006 China
| | - Huifang Fan
- grid.411868.20000 0004 1798 0690State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006 China
| | - Haifang Chen
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China.
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Liu P, Ma G, Wang Y, Wang L, Li P. Therapeutic effects of traditional Chinese medicine on gouty nephropathy: Based on NF-κB signalingpathways. Biomed Pharmacother 2023; 158:114199. [PMID: 36916428 DOI: 10.1016/j.biopha.2022.114199] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/20/2022] [Accepted: 12/30/2022] [Indexed: 01/04/2023] Open
Abstract
As the final product of purine metabolism, excess serum uric acid (SUA) aggravates the process of some metabolic diseases. SUA causes renal tubule damage, interstitial fibrosis, and glomerular hardening, leading to gouty nephropathy (GN). A growing number of investigations have shown that NF-κB mediated inflammation and oxidative stress have been directly involved in the pathogenesis of GN. Traditional Chinese medicine's treatment methods of GN have amassed a wealth of treatment experience. In this review, we first describe the mechanism of NF-κB signaling pathways in GN. Subsequently, we highlight traditional Chinese medicine that can treat GN through NF-κB pathways. Finally, commenting on promising candidate targets of herbal medicine for GN treatment via suppressing NF-κB signaling pathways was summarized.
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Affiliation(s)
- Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Station East 5, Shunyi District, Beijing 101300, China
| | - Guijie Ma
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yang Wang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Lifan Wang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China.
| | - Ping Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, China-Japan Friendship Hospital, Beijing, China.
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Mohapatra A, Rajendrakumar SK, Chandrasekaran G, Revuri V, Sathiyamoorthy P, Lee YK, Lee JH, Choi SY, Park IK. Biomineralized Nanoscavenger Abrogates Proinflammatory Macrophage Polarization and Induces Neutrophil Clearance through Reverse Migration during Gouty Arthritis. ACS APPLIED MATERIALS & INTERFACES 2023; 15:3812-3825. [PMID: 36646643 DOI: 10.1021/acsami.2c19684] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
The deposition of monosodium urate (MSU) crystals induces the overexpression of reactive oxygen species (ROS) and proinflammatory cytokines in residential macrophages, further promoting the infiltration of inflammatory leukocytes in the joints of gouty arthritis. Herein, a peroxidase-mimicking nanoscavenger was developed by forming manganese dioxide over albumin nanoparticles loaded with an anti-inflammatory drug, indomethacin (BIM), to block the secretion of ROS and COX2-induced proinflammatory cytokines in the MSU-induced gouty arthritis model. In the MSU-induced arthritis mouse model, the BIM nanoparticles alleviated joint swelling, which is attributed to the abrogation of ROS and inflammatory cytokine secretions from proinflammatory macrophages that induces neutrophil infiltration and fluid building up in the inflammation site. Further, the BIM nanoparticle treatment reduced the influx of macrophages and neutrophils in the injured region by blocking migration and inducing reverse migration in the zebrafish larva tail amputation model as well as in MSU-induced peritonitis and air pouch mouse models. Overall, the current strategy of employing biomineralized nanoscavengers for arthritis demonstrates clinical significance in dual blocking of peroxides and COX2 to prevent influx of inflammatory cells into the sites of inflammation.
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Affiliation(s)
- Adityanarayan Mohapatra
- Department of Biomedical Sciences and Center for Global Future Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju61469, Republic of Korea
| | - Santhosh Kalash Rajendrakumar
- Department of Biomedical Sciences and Center for Global Future Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju61469, Republic of Korea
- Department of Chemistry, University of Warwick, CoventryCV4 7AL, United Kingdom
| | - Gopalakrishnan Chandrasekaran
- Department of Biomedical Sciences and Center for Global Future Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju61469, Republic of Korea
| | - Vishnu Revuri
- Department of Green Bioengineering, Korea National University of Transportation, Chungju27470, Republic of Korea
| | - Padmanaban Sathiyamoorthy
- Department of Biomedical Sciences and Center for Global Future Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju61469, Republic of Korea
| | - Yong-Kyu Lee
- Department of Green Bioengineering, Korea National University of Transportation, Chungju27470, Republic of Korea
| | - Jae Hyuk Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju61469, Republic of Korea
| | - Seok-Yong Choi
- Department of Biomedical Sciences and Center for Global Future Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju61469, Republic of Korea
| | - In-Kyu Park
- Department of Biomedical Sciences and Center for Global Future Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju61469, Republic of Korea
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Allegrini S, Garcia-Gil M, Pesi R, Camici M, Tozzi MG. The Good, the Bad and the New about Uric Acid in Cancer. Cancers (Basel) 2022; 14:cancers14194959. [PMID: 36230882 PMCID: PMC9561999 DOI: 10.3390/cancers14194959] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/30/2022] [Accepted: 10/06/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The concentration of uric acid in blood is sex-, age- and diet-dependent and is maintained close to its maximal solubility, indicating that it plays some important role. Indeed, it has been demonstrated that, at physiological concentrations, uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. At high intracellular concentration, uric acid has been demonstrated to act as a pro-oxidant molecule. Recently, uric acid has been reported to affect the properties of several proteins involved in metabolic regulation and signaling, and the relationship between uric acid and cancer has been extensively investigated. In this review, we present the most recent results on the positive and negative effects played by uric acid in cancer and some new findings and hypotheses about the implication of this metabolite in the pathogenesis of several diseases such as metabolic syndrome, diabetes, and inflammation, thus favoring the development of cancer. Abstract Uric acid is the final product of purine catabolism in man and apes. The serum concentration of uric acid is sex-, age- and diet-dependent and is maintained close to its maximal solubility, indicating that it plays some important role. Indeed, it has been demonstrated that, at physiological concentrations, uric acid is a powerful antioxidant, while at high intracellular concentrations, it is a pro-oxidant molecule. In this review, we describe the possible causes of uric acid accumulation or depletion and some of the metabolic and regulatory pathways it may impact. Particular attention has been given to fructose, which, because of the complex correlation between carbohydrate and nucleotide metabolism, causes uric acid accumulation. We also present recent results on the positive and negative effects played by uric acid in cancer and some new findings and hypotheses about the implication of this metabolite in a variety of signaling pathways, which can play a role in the pathogenesis of diseases such as metabolic syndrome, diabetes, and inflammation, thus favoring the development of cancer. The loss of uricase in Homo sapiens and great apes, although exposing these species to the potentially adverse effects of uric acid, appears to be associated with evolutionary advantages.
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Affiliation(s)
- Simone Allegrini
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, Università di Pisa, 56126 Pisa, Italy
- CISUP, Centro per L’Integrazione della Strumentazione dell’Università di Pisa, 56127 Pisa, Italy
- Correspondence:
| | - Mercedes Garcia-Gil
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, Università di Pisa, 56126 Pisa, Italy
- CISUP, Centro per L’Integrazione della Strumentazione dell’Università di Pisa, 56127 Pisa, Italy
- Unità di Fisiologia Generale, Dipartimento di Biologia, Università di Pisa, Via San Zeno 31, 56127 Pisa, Italy
| | - Rossana Pesi
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
| | - Marcella Camici
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
| | - Maria Grazia Tozzi
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
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Wen H, Lu D, Chen H, Zhu Y, Xie Q, Zhang Z, Wu Z. Tetrahydropalmatine induces the polarization of M1 macrophages to M2 to relieve limb ischemia-reperfusion-induced lung injury via inhibiting the TLR4/NF-κB/NLRP3 signaling pathway. Drug Dev Res 2022; 83:1362-1372. [PMID: 35976115 DOI: 10.1002/ddr.21965] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/25/2022] [Accepted: 06/08/2022] [Indexed: 11/12/2022]
Abstract
Tetrahydropalmatine (THP) is the main component of the Chinese medicine Corydalis yanhusuo, which has been reported to alleviate limb ischemia-reperfusion-induced acute lung injury (LIR-ALI). This study aimed to investigate the mechanism underlying the effect of THP on relieving LIR-ALI. LIR-ALI model was established in rats with the presence or absence of THP pretreatment. Then, BEAS-2B cells and THP-1 macrophages were cocultured with rat serum from the Sham group and the Model group in the presence or absence of THP pretreatment. Subsequently, lung/body weight and lung wet/dry ratio of rats were calculated. Histological changes of lung tissues were observed by hematoxylin-eosin staining. Expression of CD86 and CD163 in lung tissues of rats was assessed by quantitative reverse transcription polymerase chain reaction, immunohistochemistry staining, and flow cytometry analysis. Levels of inflammatory cytokines were measured by enzyme linked immunosorbent assay. The expression of proteins related to toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB)/NLRP3 signaling was detected by western blot analysis. Results revealed that THP significantly relieved LIR-ALI in rats. Moreover, THP also reduced CD86 expression but elevated CD163 expression in lung tissues of rats with LIR-ALI. Furthermore, THP inhibited inflammation in serum and bronchoalveolar lavage fluid of rats with LIR-ALI and inactivated the TLR4/NF-κB/NLRP3 signaling in vivo. Additionally, coculture of serum from rats in the Model group also reduced viability, promoted inflammation, inactivated TLR4/NF-κB/NLRP3 expression in BEAS-2B cells and inhibited macrophage polarization, while these effects were all reversed by THP treatment. Collectively, THP could induce the polarization of M1 macrophage to M2 to suppress inflammation via inhibiting TLR4/NF-κB/NLRP3 signaling, thereby attenuating LIR-ALI.
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Affiliation(s)
- Heng Wen
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Dongshi Lu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hanjian Chen
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yeke Zhu
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qing Xie
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhao Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhouyang Wu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Wen P, Luo P, Zhang B, Zhang Y. Mapping Knowledge Structure and Global Research Trends in Gout: A Bibliometric Analysis From 2001 to 2021. Front Public Health 2022; 10:924676. [PMID: 35844867 PMCID: PMC9277182 DOI: 10.3389/fpubh.2022.924676] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/03/2022] [Indexed: 12/24/2022] Open
Abstract
Background The incidence and prevalence of gout have been steadily increasing globally, which has resulted in gout research attracting consistently increased attention. This study aimed to visualize the knowledge structure and research trends in gout research through bibliometrics to help understand the future development of basic and clinical research. Methods Articles and reviews on gout from 2001 to 2021 were extracted from the Web of Science Core Collection database. CiteSpace and VOSviewer software were used to visualize the knowledge network of countries, institutions, authors, references, and keywords in this field. SPSS and Microsoft Excel software were used for curve fitting and correlation analysis. Results A total of 3,259 articles and reviews were included. The number of publications about gout significantly increased yearly. Publications were mainly concentrated in North America, Europe, Oceania, and East Asia. The USA contributed most with 1,025 publications, followed by China and New Zealand. After adjusting for publications by population size and Gross Domestic Product (GDP), New Zealand ranked in the first place. GDP and international collaboration were significantly correlated with scientific productivity for gout research. University of Auckland and Professor Dalbeth Nicola were the most prolific institutions and influential authors, respectively. Rheumatology was the most productive journal for gout research. Gout research hotspots have shifted over time in the following order: clinical features, pathological mechanisms, complications, gouty arthritis, epidemiology, and dual-energy computed tomography to drug clinical trials, which can be observed from the keyword analysis and co-cited reference cluster analysis. Conclusions This study found that research on gout is flourishing. The development and experimentation of drugs for the prevention and treatment of gouty arthritis would be the focus of current research and developmental trends in future research.
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Affiliation(s)
- Pengfei Wen
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Pan Luo
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Binfei Zhang
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yumin Zhang
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
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Heimfarth L, Rezende MM, Pereira EWM, Passos FRS, Monteiro BS, Santos TKB, Lima NT, Souza ICL, de Albuquerque Junior RLC, de Souza Siqueira Lima P, de Souza Araújo AA, Quintans Júnior LJ, Kim B, Coutinho HDM, de Souza Siqueira Quintans J. Pharmacological effects of a complex α-bisabolol/β-cyclodextrin in a mice arthritis model with involvement of IL-1β, IL-6 and MAPK. Biomed Pharmacother 2022; 151:113142. [PMID: 35623175 DOI: 10.1016/j.biopha.2022.113142] [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: 04/05/2022] [Revised: 05/03/2022] [Accepted: 05/15/2022] [Indexed: 11/15/2022] Open
Abstract
Inflammatory arthritis is the most prevalent chronic inflammatory disease worldwide. The pathology of the disease is characterized by increased inflammation and oxidative stress, which leads to chronic pain and functional loss in the joints. Conventional anti-arthritic drugs used to relieve pain and other arthritic symptoms often cause severe side effects. α-bisabolol (BIS) is a sesquiterpene that exhibits high anti-inflammatory potential and a significant antinociceptive effect. This study evaluates the anti-arthritic, anti-inflammatory and antihyperalgesic effects of BIS alone and in a β-cyclodextrin (βCD/BIS) inclusion complex in a CFA-induced arthritis model. Following the intra-articular administration of CFA, male mice were treated with vehicle, BIS and βCD/BIS (50 mg/kg, p.o.) or a positive control and pain-related behaviors, knee edema and inflammatory and oxidative parameters were evaluated on days 4, 11, 18 and/or 25. Ours findings shows that the oral administration of BIS and βCD/BIS significantly attenuated spontaneous pain-like behaviors, mechanical hyperalgesia, grip strength deficit and knee edema induced by repeated injections of CFA, reducing the joint pain and functional disability associated with arthritis. BIS and βCD/BIS also inhibited the generation of inflammatory and oxidative markers in the knee and blocked MAPK in the spinal cord. In addition, ours results also showed that the incorporation of BIS in cyclodextrin as a drug delivery system improved the pharmacological profile of this substance. Therefore, these results contribute to the pharmacological knowledge of BIS and demonstrated that this terpene appears to be able to mitigate deleterious symptoms of arthritis.
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Affiliation(s)
- Luana Heimfarth
- Multiuser Health Center Facility (CMulti-Saúde), Federal University of Sergipe, São Cristóvão, SE, Brazil; Health Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, SE, Brazil; Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Marília Matos Rezende
- Multiuser Health Center Facility (CMulti-Saúde), Federal University of Sergipe, São Cristóvão, SE, Brazil; Health Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, SE, Brazil; Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Erik Willyame Menezes Pereira
- Multiuser Health Center Facility (CMulti-Saúde), Federal University of Sergipe, São Cristóvão, SE, Brazil; Health Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, SE, Brazil; Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Fabiolla Rocha Santos Passos
- Multiuser Health Center Facility (CMulti-Saúde), Federal University of Sergipe, São Cristóvão, SE, Brazil; Health Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, SE, Brazil; Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Brenda Souza Monteiro
- Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Tiffany Karoline Barroso Santos
- Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Natália Teles Lima
- Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Isana Carla Leal Souza
- Laboratory of Morphology and Experimental Pathology, Research and Technology Institute, Tiradentes University (UNIT), Aracaju, SE, Brazil
| | | | - Pollyana de Souza Siqueira Lima
- Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | | | - Lucindo José Quintans Júnior
- Multiuser Health Center Facility (CMulti-Saúde), Federal University of Sergipe, São Cristóvão, SE, Brazil; Health Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, SE, Brazil; Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
| | - Henrique D M Coutinho
- Department of Biological Chemistry, Regional University of Cariri - URCA, Crato, Brazil.
| | - Jullyana de Souza Siqueira Quintans
- Multiuser Health Center Facility (CMulti-Saúde), Federal University of Sergipe, São Cristóvão, SE, Brazil; Health Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, SE, Brazil; Laboratory of Neurosciences and Pharmacological Assays (LANEF), Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil.
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Zhao J, Wei K, Jiang P, Chang C, Xu L, Xu L, Shi Y, Guo S, Xue Y, He D. Inflammatory Response to Regulated Cell Death in Gout and Its Functional Implications. Front Immunol 2022; 13:888306. [PMID: 35464445 PMCID: PMC9020265 DOI: 10.3389/fimmu.2022.888306] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 03/17/2022] [Indexed: 02/03/2023] Open
Abstract
Gout, a chronic inflammatory arthritis disease, is characterized by hyperuricemia and caused by interactions between genetic, epigenetic, and metabolic factors. Acute gout symptoms are triggered by the inflammatory response to monosodium urate crystals, which is mediated by the innate immune system and immune cells (e.g., macrophages and neutrophils), the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pro-inflammatory cytokine (e.g., IL-1β) release. Recent studies have indicated that the multiple programmed cell death pathways involved in the inflammatory response include pyroptosis, NETosis, necroptosis, and apoptosis, which initiate inflammatory reactions. In this review, we explore the correlation and interactions among these factors and their roles in the pathogenesis of gout to provide future research directions and possibilities for identifying potential novel therapeutic targets and enhancing our understanding of gout pathogenesis.
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Affiliation(s)
- Jianan Zhao
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wei
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Ping Jiang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Cen Chang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Lingxia Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Linshuai Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Yiming Shi
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Shicheng Guo
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Yu Xue
- Department of Rheumatology, Huashan Hospital, Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China
| | - Dongyi He
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
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Lu Y, Fang L, Xu X, Wu Y, Li J. MicroRNA-142-3p facilitates inflammatory response by targeting ZEB2 and activating NF-κB signaling in gouty arthritis. Cell Cycle 2022; 21:805-819. [PMID: 35239453 PMCID: PMC8973338 DOI: 10.1080/15384101.2022.2031678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Gouty arthritis (GA) is caused by monosodium urate (MSU) crystal accumulation in the joints. MSU-mediated inflammation is an important inducing factor in gouty arthritis (GA). Recent studies have demonstrated that microRNAs can influence GA progression. Herein, the role and mechanism of miRNA-142-3p in GA were explored. To establish the in vitro and in vivo GA models, MSU was used to induce inflammatory response in human monocyte cell line THP-1 and male C57BL/6 mice. Protein levels, gene expression and proinflammatory cytokine secretion were respectively tested by Western blotting, RT-qPCR, and enzyme-linked immunosorbent assay (ELISA). Pathological changes in sagittal sections of ankle tissues were exhibited by hematoxylin-eosin (HE) staining. Binding relationship between miRNA-142-3p and zinc finger E-box binding homeobox 2 (ZEB2) was predicted and confirmed by bioinformatics analysis and luciferase reporter assay. In this study, MSU induced inflammatory response and upregulated miRNA-142-3p in THP-1 cells. Functionally, miRNA-142-3p knockdown inhibited inflammatory response in MSU-stimulated THP-1 cells and alleviated pathological symptoms of GA mice. Mechanically, miRNA-142-3p targeted ZEB2 in THP-1 cells. ZEB2 expression was elevated in MSU-administrated THP-1 cells and GA mice. ZEB2 downregulation reserved the inhibitory effect of miRNA-142-3p deficiency on inflammatory response in MSU-treated THP-1 cells. In addition, miRNA-142-3p activated NF-κB signaling by binding with ZEB2 in THP-1 cells upon MSU stimulation. Overall, miRNA-142-3p facilitates inflammatory response by targeting ZEB2 and activating NF-κB signaling in GA.
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Affiliation(s)
- Yao Lu
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan 316021, Zhejiang, China
| | - Li Fang
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan 316021, Zhejiang, China
| | - Xiangfeng Xu
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan 316021, Zhejiang, China,CONTACT Xiangfeng Xu Zhoushan Hospital of Zhejiang Province, No.739 Dingshen Road, Lincheng New District, Zhoushan, Zhejiang, China
| | - Yanying Wu
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan 316021, Zhejiang, China
| | - Jiajia Li
- Department of Rheumatology and Immunology, Zhoushan Hospital of Zhejiang Province, Zhoushan 316021, Zhejiang, China
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Kim H, Han S, Song K, Lee MY, Park B, Ha IJ, Lee SG. Ethyl Acetate Fractions of Papaver rhoeas L. and Papaver nudicaule L. Exert Antioxidant and Anti-Inflammatory Activities. Antioxidants (Basel) 2021; 10:antiox10121895. [PMID: 34942995 PMCID: PMC8750608 DOI: 10.3390/antiox10121895] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 02/01/2023] Open
Abstract
Abnormal inflammation and oxidative stress are involved in various diseases. Papaver rhoeas L. possesses various pharmacological activities, and a previously reported analysis of the anti-inflammatory effect of P. nudicaule ethanol extracts and alkaloid profiles of the plants suggest isoquinoline alkaloids as potential pharmacologically active compounds. Here, we investigated anti-inflammatory and antioxidant activities of ethyl acetate (EtOAc) fractions of P. nudicaule and P. rhoeas extracts in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. EtOAc fractions of P. nudicaule and P. rhoeas compared to their ethanol extracts showed less toxicity but more inhibitory activity against LPS-induced nitric oxide production. Moreover, EtOAc fractions lowered the LPS-induced production of proinflammatory molecules and cytokines and inhibited LPS-activated STAT3 and NF-κB, and additionally showed significant free radical scavenging activity and decreased LPS-induced reactive oxygen species and oxidized glutathione. EtOAc fractions of P. nudicaule increased the expression of HO-1, GCLC, NQO-1, and Nrf2 in LPS-stimulated cells and that of P. rhoeas enhanced NQO-1. Furthermore, metabolomic and biochemometric analyses of ethanol extracts and EtOAc fractions indicated that EtOAc fractions of P. nudicaule and P. rhoeas have potent anti-inflammatory and antioxidant activities, further suggesting that alkaloids in EtOAc fractions are potent active molecules of tested plants.
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Affiliation(s)
- Hail Kim
- Graduate School, Kyung Hee University, Seoul 02447, Korea; (H.K.); (S.H.)
| | - Sanghee Han
- Graduate School, Kyung Hee University, Seoul 02447, Korea; (H.K.); (S.H.)
| | - Kwangho Song
- Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02454, Korea; (K.S.); (M.Y.L.); (B.P.)
| | - Min Young Lee
- Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02454, Korea; (K.S.); (M.Y.L.); (B.P.)
| | - BeumJin Park
- Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02454, Korea; (K.S.); (M.Y.L.); (B.P.)
| | - In Jin Ha
- Graduate School, Kyung Hee University, Seoul 02447, Korea; (H.K.); (S.H.)
- Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02454, Korea; (K.S.); (M.Y.L.); (B.P.)
- Correspondence: (I.J.H.); (S.-G.L.); Tel.: +82-2-961-2355 (S.-G.L.)
| | - Seok-Geun Lee
- Graduate School, Kyung Hee University, Seoul 02447, Korea; (H.K.); (S.H.)
- Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02454, Korea; (K.S.); (M.Y.L.); (B.P.)
- Correspondence: (I.J.H.); (S.-G.L.); Tel.: +82-2-961-2355 (S.-G.L.)
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Dhar R, Rana MN, Zhang L, Li Y, Li N, Hu Z, Yan C, Wang X, Zheng X, Liu H, Cui H, Li Z, Tang H. Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury. Free Radic Biol Med 2021; 176:378-391. [PMID: 34644617 DOI: 10.1016/j.freeradbiomed.2021.10.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/03/2021] [Accepted: 10/08/2021] [Indexed: 12/22/2022]
Abstract
Acute lung injury (ALI) is associated with overproduction of inflammatory mediators in lung tissue. Previous studies have revealed that inflammation induces activation of phosphodiesterase 4B (PDE4B) accompanied by the production of inflammatory mediators, but the detailed mechanism remains unclear. Here, we focused on the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome complexes to study the crosstalk between PDE4B and NF-E2-related factor 2 (Nrf2). We used global knockout PDE4B or Nrf2 mice to prepare LPS induced acute lung injury model by intratracheally administration, and LPS primed bone marrow-derived macrophages (BMDMs), following overexpression of PDE4B or Nrf2, luciferase activity analysis, and chIP-qPCR analyses. We found that deficiency of PDE4B could potently attenuate the lung histopathological changes, suppress the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, IL-18, and cleaved caspase-1, 8, and GSDMD accompanied with defective activation of the ROS/Nrf2/NLRP3. Meanwhile deficiency of Nrf2 showed the similar results. Furtherly, overexpression by PDE4B or Nrf2 plasmid transfection in MH-S cells could enhance the Nrf2 or PDE4B expression. Luciferase analysis suggested that Nrf2 activated PDE4B promoter activity, while PDE4B could increase Nrf2 substrate ARE activity in MH-S cells in dose dependent manners. ChIP-qPCR analyses showed that Nrf2 bound to the PDE4B promoter region at ̴ 1532 to ̴1199 position in macrophages. Altogether, deficiency of PDE4B inhibit the inflammasome activation and pyroptosis in LPS stimulated lung injury model and macrophages by regulating ROS/Nrf2/NLRP3 activation. The study provides new insight that PDE4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2.
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Affiliation(s)
- Rana Dhar
- Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Mohammad Nasiruddin Rana
- Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Lejun Zhang
- Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yajun Li
- Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Ning Li
- Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Zhengqiang Hu
- Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Chungunag Yan
- Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing 210009, China
| | - Xuefeng Wang
- Department of Pharmacy, Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, China
| | - Xuyang Zheng
- Department of Pediatrics, The Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
| | - Hongyun Liu
- Institute of Dairy Science, MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Huashun Cui
- Department of Acupuncture and Moxibustion, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China.
| | - Zigang Li
- Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, China.
| | - Huifang Tang
- Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
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