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Zeng W, Sun M, Cao J, Chen C, Jiang S, Wang Y, Yang W, Zhao Z, Jin J. Triterpenoids from ilicis rotundae cortex ameliorate hyperlipidemia by affecting bile acids-hepatointestinal FXR axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156537. [PMID: 40023069 DOI: 10.1016/j.phymed.2025.156537] [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: 10/13/2024] [Revised: 01/15/2025] [Accepted: 02/16/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Hyperlipidemia is a lipid metabolism disorder that, in severe cases, can lead to conditions such as hypertension, coronary heart disease, and cirrhosis. Previous studies have identified Ilicis Rotundae Cortex (IRC) crude extract as having the potential to regulate blood lipids. However, whether the triterpenoids therein are the principal agents responsible for hypolipidemic effects and their specific mechanisms of action remain unexplored. This study aimed to investigate the effects of total triterpenoids (TT) extract derived from IRC on hyperlipidemia and to elucidate their potential mechanisms. METHODS TT extract was first prepared and characterized to assess their hypolipidemic activity in cell models. A hyperlipidemia mouse model was established by using C57BL/6 J mice fed a high-fat, high-sugar, and high-cholesterol diet for 8 weeks. TT extract was administered as a prophylactic intervention for 4 weeks to evaluate its impact on blood lipid levels, liver lipid metabolism, and liver function. Based on progressive analysis, this study integrated serum non-targeted metabolomics analysis strategy and bile acids-targeted metabolomics analysis strategy. It was combined with modern molecular biology techniques to reveal the mechanism by which TT extract ameliorated the symptoms of hyperlipidemia through a cascade approach. RESULTS TT extract treatment significantly reduced lipid levels in hyperlipidemic mice. Notably, TT extract down-regulated bile acid levels, particularly bile acids as FXR antagonists such as T-β-MCA, β-MCA, TUDCA, and UDCA. This effect is likely mediated through alterations in the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways. TT extract administration led to decreased expression of CYP7A1 and CYP7B1, resulting in reduced bile acid levels in vivo. Additionally, FXR expression was upregulated in both the liver and ileum, potentially activating FGF15 in the ileum, which in turn transmits signals to the liver and modulates SHP and BSEP expression. These changes contribute to the regulation of bile acid synthesis, metabolism, and excretion. In vitro experiments also demonstrated that TT extract influenced the protein expression of FXR and FGF19. CONCLUSION Our findings demonstrate that TT extract from IRC has hypolipidemic effects. This study is the first to reveal the mechanism by which TT extract improves hyperlipidemia from the perspective of the hepatic-intestinal axis and bile acid metabolism. Its underlying mechanism is related to activating the intestinal FXR-FGF15/19 signaling pathway, which transmits signals to the liver, thereby affecting the hepatic FXR-SHP signaling pathway. This results in improved bile acid metabolism, ultimately reducing hepatic injury and ileal inflammation to exert hypolipidemic effects.
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Affiliation(s)
- Wei Zeng
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, 519000, PR China
| | - Mengjia Sun
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, 519000, PR China
| | - Jiamin Cao
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, 519000, PR China
| | - Caixin Chen
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, 519000, PR China
| | - Shiqin Jiang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR China
| | - Yuanyuan Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, 519000, PR China
| | - Weiqun Yang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, 519000, PR China
| | - Zhongxiang Zhao
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, 519000, PR China.
| | - Jing Jin
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR China.
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Li L, Sun J, Chen F, Xiong L, She L, Hao T, Zeng Y, Li L, Wang W, Zhao X, Liang G. Pedunculoside alleviates cognitive deficits and neuronal cell apoptosis by activating the AMPK signaling cascade. Chin Med 2024; 19:163. [PMID: 39574131 PMCID: PMC11583384 DOI: 10.1186/s13020-024-01033-6] [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: 06/19/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Mitochondrial dysfunction emerges as an early pathological hallmark of Alzheimer's disease (AD). The reduction in mitochondrial membrane potential and the elevation of reactive oxygen species (ROS) production are pivotal in the initiation of neuronal cell apoptosis. Pedunculoside(Ped), a novel triterpene saponin derived from the dried barks of Ilex rotunda Thunb, exhibits a potent anti-inflammatory effect. In the course of drug screening, we discovered that Ped offers significant protection against apoptosis induced by Aβ1-42. Nevertheless, the role and mechanism of Ped in AD are yet to be elucidated. METHODS Oxidative stress was evaluated by measuring mitochondrial membrane potential and intracellular ROS production. The expression of proteins associated with apoptosis was determined using western blot analysis and flow cytometry. In vivo, the pathological characteristics of AD were investigated through Western blot and tissue immunofluorescence techniques. Cognitive function was assessed using the Morris Water Maze and Novel Object Recognition tests. RESULTS We demonstrated that Ped decreased apoptosis in PC12 cells, reduced the generation of intracellular ROS, and restored mitochondrial membrane potential. Mechanistically, we found that the protective effect of Ped against Aβ-induced neurotoxicity was associated with activation of the AMPK/GSK-3β/Nrf2 signaling pathway. In vivo, Ped alleviated memory deficits and inhibited neuronal apoptosis, inflammation, and oxidative stress in the hippocampus of 3 × Tg AD mice, along with the activation of the AMPK signaling pathway. CONCLUSION The findings indicate that Ped exerts its neuroprotective effects against oxidative stress and apoptosis through the AMPK signaling cascade. The results demonstrate that Ped is a potential candidate for the treatment of AD.
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Affiliation(s)
- Liwei Li
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Jinfeng Sun
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji, Jilin, 133002, People's Republic of China
| | - Fan Chen
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Li Xiong
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Lingyu She
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji, Jilin, 133002, People's Republic of China
| | - Tang Hao
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Yuqing Zeng
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Luyao Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, 325035, Zhejiang, China
| | - Wei Wang
- Affiliated Yongkang First People's Hospital, Hangzhou Medical College, Yongkang, 321399, Zhejiang, China
| | - Xia Zhao
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China.
| | - Guang Liang
- Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China.
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Li X, Xu R, Zhou K, Cao Q. Ameliorative effect of pedunculoside on sepsis-induced acute lung injury, inflammation and pulmonary fibrosis in mice model via suppressing AKT/NF-κB pathway. J Mol Histol 2024; 55:687-698. [PMID: 39042216 DOI: 10.1007/s10735-024-10222-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/02/2024] [Indexed: 07/24/2024]
Abstract
BACKGROUND/OBJECTIVES Sepsis-induced acute lung injury (ALI) is the typical complications of sepsis with a high global incidence and mortality. Inhibition of inflammatory response is a crucial and effective strategy for sepsis-induced ALI. Pedunculoside (PE) has been shown to have an anti-inflammatory effect on various diseases. However, the effect and mechanism of PE on sepsis-induced ALI remain unknown. MATERIALS/METHODS A mice model of sepsis-induced ALI was constructed by cecal ligation and puncture (CLP). The effect of PE on the CLP-induced mice were assessed using pathological staining, terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), reverse transcription quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA) and western blot assays. RESULTS PE reduced pathological symptoms and scores, apoptosis and the W/D ratio of lung tissues in CLP-induced mice. Besides, PE decreased the level of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α), pulmonary fibrosis and the expression of fibrosis markers. Mechanically, PE inhibited AKT/NF-κB signaling in CLP-induced mice. Activation of AKT/NF-κB pathway abolished the ameliorative effect of PE on the pathological symptoms, the release of inflammatory factors and pulmonary fibrosis of CLP-induced mice. CONCLUSION PE improved inflammation and pulmonary fibrosis by inhibiting AKT/NF-κB pathway in CLP-induced mice.
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Affiliation(s)
- Xiangbo Li
- Emergency Department, Beijing Tongren Hospital, Capital Medical University, No. 2, Xihuan South Road, Economic and Technological Development Zone, Daxing District, Beijing, 100176, China
| | - Ruiming Xu
- Emergency Department, Beijing Tongren Hospital, Capital Medical University, No. 2, Xihuan South Road, Economic and Technological Development Zone, Daxing District, Beijing, 100176, China
| | - Kaiguo Zhou
- Emergency Department, Beijing Tongren Hospital, Capital Medical University, No. 2, Xihuan South Road, Economic and Technological Development Zone, Daxing District, Beijing, 100176, China
| | - Qiumei Cao
- Emergency Department, Beijing Tongren Hospital, Capital Medical University, No. 2, Xihuan South Road, Economic and Technological Development Zone, Daxing District, Beijing, 100176, China.
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Wu L, Dong L, Zhou Z, Wang X, Lin Y, Shi X, Wang P, Xu S, Fang Z. Preclinical metabolism and metabolic drug-drug interaction profile of pedunculoside and rotundic acid. Clin Transl Sci 2024; 17:e70043. [PMID: 39392387 PMCID: PMC11469747 DOI: 10.1111/cts.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 09/04/2024] [Accepted: 09/20/2024] [Indexed: 10/12/2024] Open
Abstract
Pedunculoside and rotundic acid, the most abundant components in plants of the genus Ilex L. (Aquifoliaceae), exhibit biological and pharmacological significance in the treatment of cardiovascular diseases. However, there have been few studies on their metabolism. This study performed a systematic metabolism study of pedunculoside and rotundic acid and evaluated their potential for herb-drug interaction. Pedunculoside or rotundic acid was incubated with human liver microsomes and recombinant human metabolic enzymes, and analyzed using LC-Q-TOF/MS and LC-MS/MS. Pedunculoside was found to be the most stable in human liver microsomes, whereas rotundic acid was easily metabolized. Eight pedunculoside metabolites and six rotundic acid metabolites were detected and tentatively identified through hydroxylation, glucuronidation, acetylation, and glucose conjugation. Hydroxylation of pedunculoside is mainly catalyzed by CYP3A4/5 and partly by CYP2C8. Hydroxylation of rotundic acid is almost exclusively catalyzed by CYP3A4/5, and its glucuronidation reaction is mediated by UGT1A4. Neither pedunculoside nor rotundic acid showed CYP inhibition (IC50 values > 50 μM) with the probe substrates of major CYP isoforms during incubation with human liver microsomes. This study is the first investigation into the in vitro metabolism of pedunculoside and rotundic acid using human liver microsomes. It also aims to assess their potential as perpetrators of drug-drug interactions involving CYP enzymes. The comprehensive metabolism and drug interaction studies of pedunculoside and rotundic acid enable us to evaluate and manage potential risks with their use in pharmacotherapy.
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Affiliation(s)
- Liang Wu
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
| | - Linling Dong
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
| | - Zhu Zhou
- Department of ChemistryYork College, City University of New YorkNew YorkNew YorkUSA
| | - Xin Wang
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
| | - Yujie Lin
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
| | - Xuesong Shi
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
| | - Peijing Wang
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
| | - Suocheng Xu
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
| | - Zhiyi Fang
- School of Pharmacy, Nanjing University of Chinese MedicineNanjingChina
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Alwahsh M, Alejel R, Hasan A, Abuzaid H, Al-Qirim T. The Application of Metabolomics in Hyperlipidemia: Insights into Biomarker Discovery and Treatment Efficacy Assessment. Metabolites 2024; 14:438. [PMID: 39195534 DOI: 10.3390/metabo14080438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 08/29/2024] Open
Abstract
Hyperlipidemia is a lipid metabolism disorder that refers to increased levels of total triglycerides (TGs), cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) and decreased levels of high-density lipoprotein-cholesterol (HDL-C). It is a major public health issue with increased prevalence and incidence worldwide. The ability to identify individuals at risk of this disorder before symptoms manifest will facilitate timely intervention and management to avert potential complications. This can be achieved by employing metabolomics as an early detection method for the diagnostic biomarkers of hyperlipidemia. Metabolomics is an analytical approach used to detect and quantify metabolites. This provides the ability to explain the metabolic processes involved in the development and progression of certain diseases. In recent years, interest in the use of metabolomics to identify disease biomarkers has increased, and several biomarkers have been discovered, such as docosahexaenoic acid, glycocholic acid, citric acid, betaine, and carnitine. This review discusses the primary metabolic alterations in the context of hyperlipidemia. Furthermore, we provide an overview of recent studies on the application of metabolomics to the assessment of the efficacy of traditional herbal products and common lipid-lowering medications.
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Affiliation(s)
- Mohammad Alwahsh
- Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 17138, Jordan
| | - Rahaf Alejel
- Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 17138, Jordan
| | - Aya Hasan
- Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 17138, Jordan
| | - Haneen Abuzaid
- Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 17138, Jordan
| | - Tariq Al-Qirim
- Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 17138, Jordan
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Wu L, Li D, Wang P, Dong L, Zhang W, Xu J, Jin X. In Vitro Stability and Pharmacokinetic Study of Pedunculoside and Its Beta-CD Polymer Inclusion Complex. Pharmaceutics 2024; 16:591. [PMID: 38794253 PMCID: PMC11125186 DOI: 10.3390/pharmaceutics16050591] [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: 03/14/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 05/26/2024] Open
Abstract
Pedunculoside, a triterpene saponin derived from various Ilex species, holds potential as a treatment for cardiovascular diseases. However, its clinical application is hindered by poor bioavailability, rapid elimination, and extensive intestinal metabolism to rotundic acid. To address these issues, a water-soluble inclusion complex of pedunculoside, namely, the beta-CD polymer inclusion complex of pedunculoside (pedunculoside-βCDP), was prepared in this study, and a comparative in vitro stability and pharmacokinetic behavior study was performed between pedunculoside and pedunculoside-βCDP. Both pedunculoside and pedunculoside-βCDP exhibited the highest stability in simulated gastric fluid and simulated intestinal fluid but were readily metabolized when co-incubated with Bifidobacterium adolescentis and Bifidobacterium breve. An LC-MS/MS analytical method for the simultaneous determination of pedunculoside and rotundic acid in rat plasma was successfully established, validated, and applied to investigate the pharmacokinetic behavior after rats were intravenously administered with pedunculoside or pedunculoside-βCDP. The results indicated that pedunculoside-βCDP could significantly improve the pharmacokinetic profile of pedunculoside by increasing plasma exposure, retarding elimination, and reducing intestinal metabolism. This study enhances our understanding of pedunculoside-βCDP's metabolic fate and pharmacokinetic properties and potentially advances its further research, development, and clinical application.
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Affiliation(s)
- Liang Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Danfeng Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Peijing Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Linling Dong
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wang Zhang
- School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225009, China
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| | - Jianjun Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaoliang Jin
- Clinical Pharmacology Department, Changchun GeneScience Pharmaceutical Co., Ltd., Shanghai 200235, China
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Zeng W, Yang B, Wang Y, Sun M, Yang W, Cui H, Jin J, Zhao Z. Rotundic acid alleviates hyperlipidemia in rats by regulating lipid metabolism and gut microbiota. Phytother Res 2023; 37:5958-5973. [PMID: 37776121 DOI: 10.1002/ptr.8008] [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: 06/07/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 10/01/2023]
Abstract
Disturbances in lipid metabolism and dysbiosis of the gut microbiota play an important role in the progression of hyperlipidemia. Previous study indicated that Ilicis Rotundae Cortex possesses anti-hyperlipidemic activity, and rotundic acid (RA) identified as a key active compound to be incorporated into the body. The study aimed to evaluate the anti-hyperlipidemia effects of RA and explored its impact on gut microbiota and lipid metabolism, as well as its possible mechanisms for improving hyperlipidemia. The study methodology included a comprehensive evaluation of the effects of RA on steatosis markers of hyperlipidemia, lipid metabolism, and gut microbiota by assessing biochemical parameters and histopathology, lipidomics, 16S rRNA gene sequencing, and short-chain fatty acid (SCFA) assays. The results showed that RA effectively reduced body weight and the steatosis markers in serum and liver. Moreover, the lipidomic analysis revealed significant changes in plasmatic and hepatic lipid levels, and these were restored by RA. According to the results of 16S rRNA gene sequencing, RA supplementation raised the relative abundance of Bacteroidetes and Proteobacteria while decreasing the relative abundance of Firmicutes. RA significantly boosted the relative abundance of SCFAs by increasing SCFAs-producing bacteria such as Bacteroides, Alloprevotella, Desulfovibrio, etc. In summary, RA could regulate triglyceride metabolism and glycerophospholipid metabolism, restore gut microbiota structure, and increase the relative abundance of SCFAs-producing bacteria to exert its hypolipidemic effects. These findings suggest RA to be a promising therapeutic agent for hyperlipidemia.
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Affiliation(s)
- Wei Zeng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bao Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, Hubei Minzu University, Enshi, China
| | - Yuanyuan Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mengjia Sun
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weiqun Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui Cui
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Jin
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Zhongxiang Zhao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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Ali FE, Ibrahim IM, Ghogar OM, Abd-alhameed EK, Althagafy HS, Hassanein EH. Therapeutic interventions target the NLRP3 inflammasome in ulcerative colitis: Comprehensive study. World J Gastroenterol 2023; 29:1026-1053. [PMID: 36844140 PMCID: PMC9950862 DOI: 10.3748/wjg.v29.i6.1026] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/29/2023] [Accepted: 01/29/2023] [Indexed: 02/10/2023] Open
Abstract
One of the significant health issues in the world is the prevalence of ulcerative colitis (UC). UC is a chronic disorder that mainly affects the colon, beginning with the rectum, and can progress from asymptomatic mild inflammation to extensive inflammation of the entire colon. Understanding the underlying molecular mechanisms of UC pathogenesis emphasizes the need for innovative therapeutic approaches based on identifying molecular targets. Interestingly, in response to cellular injury, the NLR family pyrin domain containing 3 (NLRP3) inflammasome is a crucial part of the inflammation and immunological reaction by promoting caspase-1 activation and the release of interleukin-1β. This review discusses the mechanisms of NLRP3 inflammasome activation by various signals and its regulation and impact on UC.
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Affiliation(s)
- Fares E.M Ali
- Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Islam M. Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Osama M Ghogar
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Esraa K. Abd-alhameed
- Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 12345, Egypt
| | - Hanan S. Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah 12345, Saudi Arabia
| | - Emad H.M. Hassanein
- Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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Rapid Identification of the Chemical Components of Ilex rotunda Thunb Using UPLC-Q-TOF-MS/MS. J CHEM-NY 2021. [DOI: 10.1155/2021/9570776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Ilicis Rotundae Cortex (IRC) consists of the bark of Ilex rotunda Thunb, and its chemical constituents mainly include flavonoid glycosides, phenols, and triterpenoid saponins. In this study, a preliminary analysis was performed to identify and obtain the chemical components from IRC to better control the quality of the medicinal materials and provide a chemical basis for the study of the efficacy of the active components. Simple and efficient sample pretreatment and ultrasonic-assisted extraction methods were used to analyze the mass spectrum fragments and fracture modes in the anion mode by UPLC-Q-TOF-MS/MS. Using a two-step strategy, the neutral loss, diagnostic ions, and characteristic fragments were studied to screen diverse skeletons and substitutions, and the possible compounds were identified by comparison with databases. The representative compounds were compared with the standard, and the mass spectrogram was found to match perfectly. Thus, our findings reveal that this method is feasible and reliable and can be used to analyze the chemical components of IRC. We identified 105 compounds, including 22 triterpenoid saponins, 15 chlorogenic acids, 33 phenylpropanoids and phenylpropanosides, 3 iridoids, 1 flavonoid, 10 lignans, 12 glycosides, and 9 other compounds. This method lays the foundation for further elucidating the pharmacodynamics of IRC and provides a practical method for the identification of IRC.
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Kan X, Hu G, Huang B, Guo W, Huang Y, Chen Y, Xu P, Cai X, Fu S, Liu J. Pedunculoside protects against LPS-induced mastitis in mice by inhibiting inflammation and maintaining the integrity of blood-milk barrier. Aging (Albany NY) 2021; 13:19460-19474. [PMID: 34383710 PMCID: PMC8386561 DOI: 10.18632/aging.203357] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/14/2021] [Indexed: 04/17/2023]
Abstract
Mastitis is a disease that seriously threatens the health of the mammary gland after delivery. Pedunculoside (PE) is the main bioactive component of Aquifoliaceae. The purpose of this experiment is to explore the effects of PE on mastitis and its underlying mechanisms. Our research results showed that PE could significantly inhibit the increase in the levels of inflammatory mediators such as TNF-α, IL-6, IL-1β, MPO and iNOS during mastitis. Mechanism studies have found that PE could significantly inhibit the phosphorylation of AKT protein and binds to the ASP-184 site. Further research found that PE also inhibited the activation of AKT's downstream pro-inflammatory signals NF-κB and MAPK. In addition, PE effectively promote the expression of tight junction proteins occludin and claudin-3 during inflammation, maintaining the integrity of the blood-milk barrier. In summary, our research shows that PE inhibits the phosphorylation of AKT/NF-κB and MAPK signals; It also relieves mastitis by repairing the blood-milk barrier.
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Affiliation(s)
- Xingchi Kan
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Guiqiu Hu
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Bingxu Huang
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Wenjin Guo
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Yaping Huang
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Yingsheng Chen
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Ping Xu
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Xiangyu Cai
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Shoupeng Fu
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Juxiong Liu
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
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Shang H, Dai X, Li M, Kai Y, Liu Z, Wang M, Li Q, Gu Y, Liu C, Si D. Absolute bioavailability, dose proportionality, and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method. J Pharm Anal 2021; 12:278-286. [PMID: 35582394 PMCID: PMC9091740 DOI: 10.1016/j.jpha.2021.03.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/23/2021] [Accepted: 03/24/2021] [Indexed: 12/16/2022] Open
Abstract
Rotundic acid (RA), an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb. (Aquifoliaceae), possesses diverse bioactivities. To further study its pharmacokinetics, a simple and sensitive liquid chromatography with triple quadrupole mass spectrometry (LC-QqQ-MS/MS) method was developed and validated to quantify RA concentration in rat plasma and tissue using etofesalamide as an internal standard (IS). Plasma and tissue samples were subjected to one-step protein precipitation. Chromatographic separation was achieved on a ZORBAX Eclipse XDB-C18 column (4.6 mm × 50 mm, 5 μm) under gradient conditions with eluents of methanol:acetonitrile (1:1, V/V) and 5 mM ammonium formate:methanol (9:1, V/V) at 0.5 mL/min. Multiple reaction monitoring transitions were performed at m/z 487.30 → 437.30 for RA and m/z 256.10 → 227.10 for IS in the negative mode. The developed LC-QqQ-MS/MS method exhibited good linearity (2–500 ng/mL) and was fully validated in accordance with U.S. Food and Drug Administration bioanalytical guidelines. Dose proportionality and bioavailability in rats were determined by comparing pharmacokinetic data after single oral (10, 20, and 40 mg/kg) and intravenous (10 mg/kg) administration of RA. Tissue distribution was studied following oral administration at 20 mg/kg. The results showed that the absolute bioavailability of RA after administration at different doses ranged from 16.1% to 19.4%. RA showed good dose proportionality over a dose range of 10–40 mg/kg. RA was rapidly absorbed in a dose-dependent manner and highly distributed in the liver. In conclusion, this study is the first to systematically elucidate the absorption and distribution characteristics of RA in rats, which can provide additional information for further development and evaluation of RA in drug metabolism and pharmacokinetic studies.
A simple, rapid, and sensitive LC-QqQ-MS/MS method was developed and validated for RA quantification in rat plasma and tissue. Absolute bioavailability of RA was calculated to range from 16.1% to 19.4%. Dose proportionality and tissue distribution of RA were assessed for in rats. RA showed good dose proportionality over a dose range of 10–40 mg/kg. RA was rapidly and extensively distributed and exhibited the highest concentration in the liver after oral administration.
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Rotundic Acid Protects against Metabolic Disturbance and Improves Gut Microbiota in Type 2 Diabetes Rats. Nutrients 2019; 12:nu12010067. [PMID: 31887996 PMCID: PMC7019423 DOI: 10.3390/nu12010067] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 12/12/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023] Open
Abstract
Rotundic acid (RA) is a major triterpene constituent in the barks of Ilex rotunda Thunb, which have been widely used to make herbal tea for health care in southern China. RA has a variety of bioactivities such as anti-inflammation and lipid-lowering effect. However, little is known about the effects and mechanisms of RA on metabolic disturbance in type 2 diabetes (T2D) and its effect on gut microbiota. A T2D rat model induced by high fat diet (HFD) feeding and low-dose streptozotocin (STZ) injection was employed and RA showed multipronged effects on T2D and its complications, including improving glucolipid metabolism, lowering blood pressure, protecting against cardiovascular and hepatorenal injuries, and alleviating oxidative stress and inflammation. Furthermore, 16s rRNA gene sequencing was carried out on an Illumina HiSeq 2500 platform and RA treatment could restore the gut microbial dysbiosis in T2D rats to a certain extent. RA treatment significantly enhanced the richness and diversity of gut microbiota. At the genus level, beneficial or commensal bacteria Prevotella, Ruminococcus, Leuconostoc and Streptococcus were significantly increased by RA treatment, while RA-treated rats had a lower abundance of opportunistic pathogen Klebsiella and Proteus. Spearman’s correlation analysis showed that the abundances of these bacteria were strongly correlated with various biochemical parameters, suggesting that the improvement of gut microbiota might help to prevent or attenuate T2D and its complication. In conclusion, our findings support RA as a nutraceutical agent or plant foods rich in this compound might be helpful for the alleviation of T2D and its complications through improving gut microbiota.
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