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Ali MY, Zamponi GW, Abdul QA, Seong SH, Min BS, Jung HA, Choi JS. Prunin from Poncirus trifoliata (L.) Rafin Inhibits Aldose Reductase and Glucose-Fructose-Mediated Protein Glycation and Oxidation of Human Serum Albumin. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:7203-7218. [PMID: 38518258 DOI: 10.1021/acs.jafc.3c09716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2024]
Abstract
Diabetes complications are associated with aldose reductase (AR) and advanced glycation end products (AGEs). Using bioassay-guided isolation by column chromatography, 10 flavonoids and one coumarin were isolated from Poncirus trifoliata Rafin and tested in vitro for an inhibitory effect against human recombinant AR (HRAR) and rat lens AR (RLAR). Prunin, narirutin, and naringin inhibited RLAR (IC50 0.48-2.84 μM) and HRAR (IC50 0.68-4.88 μM). Docking simulations predicted negative binding energies and interactions with the RLAR and HRAR binding pocket residues. Prunin (0.1 and 12.5 μM) prevented the formation of fluorescent AGEs and nonfluorescent Nε-(carboxymethyl) lysine (CML), as well as the fructose-glucose-mediated protein glycation and oxidation of human serum albumin (HSA). Prunin suppressed the formation of the β-cross-amyloid structure of HSA. These results indicate that prunin inhibits oxidation-dependent protein damage, AGE formation, and AR, which may help prevent diabetes complications.
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Affiliation(s)
- Md Yousof Ali
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary T2N 4N1, AB, Canada
| | - Gerald W Zamponi
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary T2N 4N1, AB, Canada
| | - Qudeer Ahmed Abdul
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Su Hui Seong
- Natural Products Research Division, Honam National Institute of Biological Resources, Mokpo 58762, Republic of Korea
| | - Byung-Sun Min
- Drug Research and Development Center, College of Pharmacy, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea
| | - Hyun Ah Jung
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Jae Sue Choi
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
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Zhou P, Wang X, Sun M, Yan S. Effects of natural products on functional constipation: analysis of active ingredient and mechanism. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2083-2103. [PMID: 37870581 DOI: 10.1007/s00210-023-02786-x] [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: 09/22/2023] [Accepted: 10/12/2023] [Indexed: 10/24/2023]
Abstract
Constipation is a prevalent clinical ailment of the gastrointestinal system, yet its pathogenesis remains ambiguous. Despite the availability of numerous treatment modalities, they are insufficient in resolving the issue for patients. This work conducted a comprehensive review of the existing literature pertaining to the utilization of natural products for the treatment of constipation, with a focus on the efficacy of natural products in treating constipation, and to provide a comprehensive summary of their underlying mechanisms of action. Upon conducting a thorough review of the extant literature, we found that natural products can effectively treat constipation as modern synthetic drugs and compounded drugs with acetylcholinesterase (AChE) effects, rich in fiber and mucus, and the effects of increasing the tension of the ileum and gastrointestinal tract muscle, mediating signaling pathways, cytokine, excitability of the smooth muscle of the gastrointestinal tract, and regulating the homeostasis of intestinal flora. However, there is a wide variety of natural products, and there are still relatively few studies; the composition of natural products is complex, and the mechanism of action of natural products cannot be clarified. In the future, we need to further improve the detailed mechanism of natural products for the treatment of constipation.
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Affiliation(s)
- Pengfei Zhou
- Department of Anorectal Surgery, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaopeng Wang
- Department of Anorectal surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Mingming Sun
- Department of Anorectal surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Shuai Yan
- Department of Anorectal surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
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Choi NR, Lee K, Seo M, Ko SJ, Choi WG, Kim SC, Kim J, Park JW, Kim BJ. Network Pharmacological Analysis and Experimental Validation of the Effect of Smilacis Glabrae Rhixoma on Gastrointestinal Motility Disorder. PLANTS (BASEL, SWITZERLAND) 2023; 12:1509. [PMID: 37050134 PMCID: PMC10096900 DOI: 10.3390/plants12071509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/21/2023] [Accepted: 03/29/2023] [Indexed: 06/19/2023]
Abstract
Gastrointestinal motility disorder (GMD) is a disease that causes digestive problems due to inhibition of the movement of the gastrointestinal tract and is one of the diseases that reduce the quality of life of modern people. Smilacis Glabrae Rhixoma (SGR) is a traditional herbal medicine for many diseases and is sometimes prescribed to improve digestion. As a network pharmacological approach, we searched the TCMSP database for SGR, reviewed its constituents and target genes, and analyzed its relevance to gastrointestinal motility disorder. The effects of the SGR extract on the pacemaker activity in interstitial cells of Cajal (ICC) and gastric emptying were investigated. In addition, using the GMD mouse model through acetic acid (AA), we investigated the locomotor effect of SGR on the intestinal transit rate (ITR). As a result of network pharmacology analysis, 56 compounds out of 74 candidate compounds of SGR have targets, the number of targets is 390 targets, and there are 904 combinations. Seventeen compounds of SGR were related to GMD, and as a result of comparing the related genes with the GMD-related genes, 17 genes (active only) corresponded to both. When looking at the relationship network between GMD and SGR, it was confirmed that quercetin, resveratrol, SCN5A, TNF, and FOS were most closely related to GMD. In addition, the SGR extract regulated the pacemaker activity in ICC and recovered the delayed gastric emptying. As a result of feeding the SGR extract to AA-induced GMD mice, it was confirmed that the ITR decreased by AA was restored by the SGR extract. Through network pharmacology, it was confirmed that quercetin, resveratrol, SCN5A, TNF, and FOS were related to GMD in SGR, and these were closely related to intestinal motility. Based on these results, it is suggested that SGR in GMD restores digestion through the recovery of intestinal motility.
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Affiliation(s)
- Na-Ri Choi
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (N.-R.C.); (M.S.); (W.-G.C.)
| | - Kangwook Lee
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul 02447, Republic of Korea; (K.L.); (S.-J.K.); (J.K.)
| | - Mujin Seo
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (N.-R.C.); (M.S.); (W.-G.C.)
| | - Seok-Jae Ko
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul 02447, Republic of Korea; (K.L.); (S.-J.K.); (J.K.)
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Woo-Gyun Choi
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (N.-R.C.); (M.S.); (W.-G.C.)
| | - Sang-Chan Kim
- College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea;
| | - Jinsung Kim
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul 02447, Republic of Korea; (K.L.); (S.-J.K.); (J.K.)
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae-Woo Park
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul 02447, Republic of Korea; (K.L.); (S.-J.K.); (J.K.)
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Byung-Joo Kim
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (N.-R.C.); (M.S.); (W.-G.C.)
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Lamichhane G, Pandey J, Devkota HP. Bioactive Chemical Constituents and Pharmacological Activities of Ponciri Fructus. Molecules 2022; 28:255. [PMID: 36615447 PMCID: PMC9821892 DOI: 10.3390/molecules28010255] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/15/2022] [Accepted: 12/22/2022] [Indexed: 12/31/2022] Open
Abstract
Ponciri Fructus is a crude drug obtained from the dried immature fruits of Poncirus trifoliata (L). Raf. (Syn. Citrus trifoliata L.). This study aims to compile and analyze the ethnomedicinal uses, bioactive constituents, and pharmacological activities of Ponciri Fructus. Various online bibliographic databases namely, SciFinder, PubMed, Google Scholar, and Web of Science were used for collecting information on traditional uses, biological activities, and bioactive constituents. Concerning ethnomedicinal uses, Ponciri Fructus is extensively used in traditional Korean, Chinese, and Kampo medicines to mitigate allergic reactions, inflammation, edema, digestive complications, respiratory problems, spleen-related problems, liver complications, neuronal pain, hyperlipidemia, rheumatoid arthritis, cardiovascular problems, hernia, sinusitis, and insomnia. Several studies have shown that Ponciri Fructus is a major source of diverse classes of bioactive compounds namely flavonoids, terpenoids, coumarins, phytosterols, and alkaloids. Several in vivo and in vitro pharmacological activity evaluations such as antidiabetic, anti-obesity, anti-inflammatory, antiallergic, antimelanogenic, gastroprotective, anticancer, and neuroprotective effects have been conducted from Ponciri Fructus. However, scientific investigations focusing on bioassay-guided isolation and identification of specific bioactive constituents are limited. Therefore, an in-depth scientific investigation of Ponciri Fructus focusing on bioassay-guided isolation, mechanism based pharmacological studies, pharmacokinetic studies, and evaluation of possible toxicities is necessary in the future.
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Affiliation(s)
- Gopal Lamichhane
- Department of Oriental Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan 570-749, Republic of Korea
| | - Jitendra Pandey
- Department of Pharmacy, Crimson College of Technology, Pokhara University, Devinagar-11, Butwal 32900, Nepal
| | - Hari Prasad Devkota
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Headquarters for Admissions and Education, Kumamoto University, Kurokami, 2-39-1, Chuo-ku, Kumamoto 860-8555, Japan
- Pharmacy Program, Gandaki University, Pokhara 33700, Nepal
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Hwang SJ, Wang JH, Lee JS, Lee HD, Choi TJ, Choi SH, Son CG. Yeokwisan, a Standardized Herbal Formula, Enhances Gastric Emptying via Modulation of the Ghrelin Pathway in a Loperamide-induced Functional Dyspepsia Mouse Model. Front Pharmacol 2021; 12:753153. [PMID: 34630123 PMCID: PMC8493126 DOI: 10.3389/fphar.2021.753153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/09/2021] [Indexed: 12/03/2022] Open
Abstract
Background: Yeokwisan, a standardized herbal formula, has exhibited clinical benefit for patients suffering from refractory functional dyspepsia (FD) in Korea since 2016. However, data about the mechanism of action of this formula are yet not available. Aim of the study: To evaluate and explore the effects of Yeokwisan on gastric emptying, a major symptom of functional dyspepsia, and its underlying mechanisms of action using a mouse model. Materials and methods: BALB/C mice were pretreated with Yeokwisan (100, 200, and 400 mg/kg, po) or mosapride (3 mg/kg, po) for 5 days and then treated with loperamide (10 mg/kg, ip) after 20 h of fasting. A solution of 0.05% phenol red (500 μL) or diet of 5% charcoal (200 μL) was orally administered, followed by assessment of gastric emptying or intestinal transit. Plasma acyl-ghrelin (ELISA), C-kit (immunofluorescence and western blotting), nNOS (western blotting) and gastric contraction- and ghrelin-related gene/protein expression levels were examined in stomach and small intestine tissues. Results: Loperamide injection substantially delayed gastric emptying, while Yeokwisan pretreatment (especially 200 and 400 mg/kg Yeokwisan) significantly attenuated this peristaltic dysfunction, as evidenced by the quantity of phenol red retained in the stomach (p < 0.05 or 0.01) and stomach weight (p < 0.05 or 0.01). The levels of plasma acyl-ghrelin and expression of gastric ghrelin-related genes, such as growth hormone secretagogue receptor (GHSR), ghrelin-O-acyltransferase (GOAT), adrenergic receptor β1 (ADRB1) and somatostatin receptor (SSTR), were significantly normalized (p < 0.05 or 0.01) by Yeokwisan (400 mg/kg). Yeokwisan (400 mg/kg) significantly tempered the loperamide-induced alterations in the c-kit and nNOS levels (p < 0.01) as well as the expression of contraction- and ghrelin-related genes, such as 5-HT4 receptor (5-HT4R), anoctamin-1 (ANO1), ryanodine receptor 3 (RYR3) and smooth muscle myosin light chain kinase (smMLCK), in the stomach, but not in the small intestine. Conclusion: The present results showed the clinical relevance of Yeokwisan, in treating FD, especially in promoting gastric emptying but not small intestinal transit. The main mechanisms corresponding to these effects may involve the modulation of the ghrelin pathway and activation of interstitial cells of Cajal in stomach tissue.
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Affiliation(s)
- Seung-Ju Hwang
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Daejeon, South Korea
| | - Jing-Hua Wang
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Daejeon, South Korea
| | - Jin-Seok Lee
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Daejeon, South Korea
| | - Hwa-Dong Lee
- National Institute for Korean Medicine, Daejeon, South Korea
| | | | - Seo-Hyung Choi
- Department of Internal Medicine, Gangnam Weedahm Korean Medical Hospital, Daejeon, South Korea
| | - Chang-Gue Son
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Daejeon, South Korea
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Sun Y, Shi H, Hong Z, Chi P. Inhibition of JAK1 mitigates postoperative ileus in mice. Surgery 2019; 166:1048-1054. [DOI: 10.1016/j.surg.2019.07.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/02/2019] [Accepted: 07/22/2019] [Indexed: 12/31/2022]
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Yeung HY, Iyer P, Pryor J, Nicholson M. Dietary management of neurogenic bowel in adults with spinal cord injury: an integrative review of literature. Disabil Rehabil 2019; 43:1208-1219. [PMID: 31415185 DOI: 10.1080/09638288.2019.1652702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE To examine the literature for current evidence on the dietary management of neurogenic bowel in adults with spinal cord injuries (SCIs). BACKGROUND Neurogenic bowel dysfunction presenting as faecal incontinence or constipation is a common occurrence in individuals with SCI. It poses numerous challenges for the management of bowel function and has a significant impact on quality of life following SCI. Dietary management is a common, early treatment strategy as a conservative approach for neurogenic bowel; however, current recommendations rely on expert opinion only. METHODS An integrative review of the literature using a systematic search was conducted using Medline, Embase, CINAHL, Proquest, and Google Scholar. The selected articles were critically appraised using Critical Appraisal Skills Programme checklists by two independent reviewers. The risk of bias of studies and the quality of evidence for outcomes were assessed using the risk of bias tool and the grading of recommendations, assessment, development, and evaluation system in the Cochrane handbook for systematic review of interventions. RESULTS Thirteen studies that met the inclusion criteria were identified exploring a variety of diet-related factors: foods, dietary behaviours, and multiple interventions including a diet plan. However, the dietary management strategies used varied significantly between studies, posing challenges to ascertain its efficacy. CONCLUSION Given the low level of evidence and paucity of data on dietary management of neurogenic bowel, the efficacy of dietary strategies (alone or in combination with others) in managing neurogenic bowel cannot be substantiated from the studies identified. Therefore, more robust studies are warranted to bridge this gap.IMPLICATIONS FOR REHABILITATIONConsumption of ∼15 g dietary fibre is shown to be beneficial in managing neurogenic bowel in SCI.Further research is required to strengthen evidence for fibre recommendations and investigating the potential benefits of traditional and non-traditional dietary approaches.
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Affiliation(s)
- Hiu Yan Yeung
- Nutrition and Dietetics, University of Sydney, Sydney, Australia
| | - Priya Iyer
- Nutrition and Dietetics, Royal Rehab Centre Sydney, Sydney, Australia
| | - Julie Pryor
- Nursing Research and Development, Royal Rehab Centre Sydney, Sydney, Australia
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Kim M, Seol MH, Lee BC. The Effects of Poncirus fructus on Insulin Resistance and the Macrophage-Mediated Inflammatory Response in High Fat Diet-Induced Obese Mice. Int J Mol Sci 2019; 20:ijms20122858. [PMID: 31212747 PMCID: PMC6628178 DOI: 10.3390/ijms20122858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/09/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023] Open
Abstract
Obesity is a chronic low-grade inflammatory condition in which hypertrophied adipocytes and adipose tissue immune cells, mainly macrophages, contribute to increased circulating levels of proinflammatory cytokines. Obesity-associated chronic low-grade systemic inflammation is considered a focal point and a therapeutic target in insulin resistance and metabolic diseases. We evaluate the effect of Poncirus fructus (PF) on insulin resistance and its mechanism based on inflammatory responses in high-fat diet (HFD)-induced obese mice. Mice were fed an HFD to induce obesity and then administered PF. Body weight, epididymal fat and liver weight, glucose, lipid, insulin, and histologic characteristics were evaluated to determine the effect of PF on insulin resistance by analyzing the proportion of macrophages in epididymal fat and liver and measured inflammatory gene expression. PF administration significantly decreased the fasting and postprandial glucose, fasting insulin, HOMA-IR, total-cholesterol, triglycerides, and low-density lipoprotein cholesterol levels. The epididymal fat tissue and liver showed a significant decrease of fat accumulation in histological analysis. PF significantly reduced the number of adipose tissue macrophages (ATMs), F4/80+ Kupffer cells, and CD68+ Kupffer cells, increased the proportion of M2 phenotype macrophages, and decreased the gene expression of inflammatory cytokines. These results suggest that PF could be used to improve insulin resistance through modulation of macrophage-mediated inflammation and enhance glucose and lipid metabolism.
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Affiliation(s)
- Mia Kim
- Department of Cardiovascular and Neurologic Disease (Stroke Center), College of Korean Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun, Seoul 02447, Korea.
| | - Mi Hyeon Seol
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.
| | - Byung-Cheol Lee
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.
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Jang Y, Kim EK, Shim WS. Phytotherapeutic effects of the fruits of Poncirus trifoliata (L.) Raf. on cancer, inflammation, and digestive dysfunction. Phytother Res 2017; 32:616-624. [PMID: 29250842 DOI: 10.1002/ptr.6008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/24/2017] [Accepted: 11/14/2017] [Indexed: 12/15/2022]
Abstract
Poncirus trifoliata (L.) Raf. belongs to the family Rutaceae in the genus Poncirus. Its fruits are widely used to alleviate symptoms of various disorders. The mature fruit (MF) possesses anticancer and antiinflammatory activities. Extracts of the dried, immature fruit, Poncirus fructus (PF) are widely used as a traditional medicine for ameliorating symptoms of digestive dysfunction in East Asia. Molecular and cellular mechanisms underlying the effects of MF and PF extracts on cancer, inflammation, and gastrointestinal disorders have been extensively studied in the past decade. This review summarizes recent findings on the anticancer and antiinflammatory effects of MF and the prokinetic effects of PF. Although the therapeutic effects of MF and PF have been clearly elucidated, in-depth further clinical studies are still required to completely verify the clinical efficacy and safety of the fruits of P. trifoliata (L.) Raf.
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Affiliation(s)
- Yongwoo Jang
- McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA
| | - Eun-Kyung Kim
- Genosco, 767C Concord Ave, Cambridge, MA, 02138, USA
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea
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Wang B, Sun X, Wang S, Guo P, Li S, Zhang M, Zhao L, Chen X. Comparative pharmacokinetics of (S)-MP3950, a novel 5-HT4 receptor agonist, in normal and atropine-induced gastrointestinal motility disorders rats. Xenobiotica 2017; 48:824-830. [PMID: 28786731 DOI: 10.1080/00498254.2017.1365974] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
1. (S)-MP3950 is the (S)-enantiomer of active metabolite of mosapride, which exhibits higher 5-HT4 receptor agonistic effect than mosapride. It shows promise to become a novel drug candidate for the treatment of gastrointestinal motility disorders (GMDs). However, the pharmacokinetic behavior of (S)-MP3950 in the pathological state of GMDs remains unclear. Herein, we investigated the comparative pharmacokinetics of (S)-MP3950 in normal and GMDs rats. 2. The comparative pharmacokinetics of (S)-MP3950 in normal and atropine-induced GMD rats were studied by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The validated UPLC-MS/MS method was successfully applied to investigate the pharmacokinetic profiles of (S)-MP3950 in normal and atropine-induced GMDs rats. Results showed that comparing to normal rats, Cmax reduced by 73.8%, AUC0-t decreased by 57.6% and AUC0-∞ declined by 56.8% in model rats. Additionally, the elimination half-life (t1/2) and Tmax were prolonged slightly. 3. The pharmacokinetic results demonstrated that the atropine-induced GMDs reduced the absorption of (S)-MP3950. The pharmacokinetics research in the pathological state might provide more useful information for further study of novel gastric motility candidates.
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Affiliation(s)
- Binjie Wang
- a Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and
| | - Xiaoyang Sun
- a Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and
| | - Shixiao Wang
- a Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and
| | - Ping Guo
- a Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and
| | - Shujuan Li
- a Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and
| | - Meiyu Zhang
- b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China
| | - Longshan Zhao
- a Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and
| | - Xiaohui Chen
- a Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and
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Prokinetic effects of LD02GIFRO on functional gastrointestinal disorder in rats. Exp Ther Med 2017; 13:2043-2049. [PMID: 28565806 DOI: 10.3892/etm.2017.4185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 11/18/2016] [Indexed: 12/24/2022] Open
Abstract
LD02GIFRO is a novel prokinetic agent formulated with Poncirus fructus and Zanthoxylum sp. fruits. The aim of the present study was to evaluate the effect of LD02GIFRO on delayed gastrointestinal transit (GIT) and colorectal hypersensitivity. To investigate the effect of LD02GIFRO, a rat model of delayed GIT was induced via three mechanisms; postoperative ileus (POI), morphine, and POI plus morphine. Visceromotor responses (VMR) to colorectal distension (CRD) were also evaluated. POI was induced by laparotomy surgery and manipulation of the small intestine under anesthesia, and GIT was calculated by measuring the length that Evans Blue travelled through the gastrointestinal tract in a given time. Oral administration of 260 mg/kg LD02GIFRO caused Evans Blue to migrate significantly further in the delayed GIT models induced by POI, morphine and POI plus morphine compared with the control (P<0.05). This effect was inhibited by atropine, a muscarinic receptor antagonist, and completely abolished by GR125487, a 5-HT4-receptor antagonist. Furthermore, intraperitoneal administration of 600 and 900 mg/kg LD02GIFRO significantly reduced VMR to CRD in acute and chronic colorectal hypersensitive rat models, induced by acetic acid and trinitrobenzenesulfonic acid, to almost normal levels (P<0.01). In the present study, LD02GIFRO successfully ameliorated delayed GIT models and colorectal hypersensitivity models, suggesting that LD02GIFRO may be an effective therapeutic treatment for patients with functional gastrointestinal disorders and abnormalities in GIT.
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Effects and Safety of Aqueous Extract of Poncirus fructus in Spinal Cord Injury with Neurogenic Bowel. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:7154616. [PMID: 27738444 PMCID: PMC5055929 DOI: 10.1155/2016/7154616] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 08/22/2016] [Indexed: 12/14/2022]
Abstract
Objective. To investigate the effects and safety of the aqueous extract of the dried, immature fruit of Poncirus trifoliata (L.) Raf., known as Poncirus fructus (PF), in spinal cord injury (SCI) patients with neurogenic bowel. Methods. Thirty-one SCI patients with neurogenic bowel were recruited. Patients were evaluated based on clinical information, constipation score, Bristol Stool Form Scale, stool retention score using plain abdominal radiograph, and colon transit time. PF was administered in dosages of 800 mg each prior to breakfast and lunch for 14 days. Results. The morphological feature of the stool before and after administration indicated a statistically significant difference from 3.52 ± 1.33 to 4.32 ± 1.44 points (p < 0.05). Stool retention score before and after administration of PF was represented with low significance (7.25 ± 1.60 to 6.46 ± 1.53 points) in the whole colon (p < 0.05), and the colon transit time was significantly shortened (57.41 ± 20.7 to 41.2 ± 25.5 hours) in terms of the whole transit time (p < 0.05). Side effects were observed in 7 people (28.0%) consisting of 2 people with soft stools and 5 people with diarrhea. Conclusion. For SCI patients, PF administration significantly improved defecation patterns, defecation retention, and colon transit time. PF could be an effective aid to improve colonic motility and constipation.
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Kim HJ, Park SY, Kim DG, Park SH, Lee H, Hwang DY, Jung MH, Ha KT, Kim BJ. Effects of the roots of Liriope Platyphylla Wang Et tang on gastrointestinal motility function. JOURNAL OF ETHNOPHARMACOLOGY 2016; 184:144-153. [PMID: 26969403 DOI: 10.1016/j.jep.2016.03.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 03/07/2016] [Accepted: 03/07/2016] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liriope platyphylla Wang et Tang continues to be used in Korea as a traditional medicine for the treatment of gastrointestinal (GI) disorders related to constipation and abnormal GI motility. AIM OF THE STUDY Because GI disorders, especially GI motility dysfunctions, are major lifelong problems, the authors investigated the effects of a water extract of the roots of L. platyphylla Wang et Tang (LPE) on the pacemaker potentials (PPTs) of interstitial cells of Cajal (ICCs) and on GI motility in male ICR mice. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record PPTs generated by cultured ICCs in vitro. In vivo effects of LPE on GI motility were investigated by measuring intestinal transit rates (ITRs) of Evans blue in normal mice and in acetic acid (AA) and streptozotocin (STZ)-induced diabetic mouse models of GI motility dysfunction. RESULTS LPE dose-dependently depolarized PPTs in ICCs. Pretreatment with methoctramine (a muscarinic M2 receptor antagonist) did not block LPE-induced PPT depolarization. However, pretreatment with 4-DAMP (a muscarinic M3 receptor antagonist) blocked LPE-induced PPT depolarization. In addition, treatment with LY294002 (a phosphoinositide 3-kinase (PI3K) inhibitor) also blocked LPE-induced PPT depolarization. Intracellular GDPβS inhibited LPE-induced PPT depolarization, and LPE-induced PPT depolarization was found to occur in a phospholipase C (PLC)- and a protein kinase C (PKC)-dependent manner. Pretreatment with Ca(2+)free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in endoplasmic reticulum) abolished PPTs, and under these conditions, LPE did not depolarize ICC PPTs. In normal mice, ITRs were significantly and dose-dependently increased by LPE (0.01-1g/kg administered intragastrically (i.g.)). In addition, LPE (i.g.) significantly recovered GI motility dysfunctions in both animal models. CONCLUSION LPE dose-dependently depolarizes ICC PPTs through M3 receptors via external and internal Ca(2+)regulation and via G protein-, PI3K-, PLC- and PKC- dependent pathways in vitro. Also, in vivo, LPE increased ITRs in treatment naïve mice and our two mouse models of GI dysfunction. Therefore, this study shows that LPE offers a basis for the development of a prokinetic agent that prevents or alleviates GI motility dysfunctions.
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Affiliation(s)
- Hyun Jung Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Sun Young Park
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Dae Geon Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - So-Hae Park
- College of Human Ecology, Pusan National University, Busan 609-735, Republic of Korea
| | - Heeseob Lee
- College of Human Ecology, Pusan National University, Busan 609-735, Republic of Korea
| | - Dae Youn Hwang
- College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang 627-706, Republic of Korea
| | - Myeong Ho Jung
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Ki-Tae Ha
- Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea; Division of Applied Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea.
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Wang SY, Liu YP, Fan YH, Zhang L, Cai LJ, Lv B. Mechanism of aqueous fructus aurantii immaturus extracts in neuroplexus of cathartic colons. World J Gastroenterol 2015; 21:9358-66. [PMID: 26309361 PMCID: PMC4541387 DOI: 10.3748/wjg.v21.i31.9358] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 05/21/2015] [Accepted: 06/26/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the effect of aqueous fructus aurantii immaturus (FAI) extracts on the intestinal plexus of cathartic colons. METHODS Cathartic colons were induced in rats with dahuang, a laxative used in traditional Chinese medicine. Once the model was established (after approximately 12 wk), rats were administered mosapride (1.54 mg/kg) or various doses of aqueous FAI extracts (1-4 g/kg) for 14 d. Transit function was assessed using an ink propulsion test. Rats were then sacrificed, and the ultramicrostructure of colonic tissue was examined using transmission electron microscopy. The expression of the 5-hydroxytryptamine receptor 4 (5-HTR4) and neurofilament-H was assessed in colon tissues using real-time PCR, Western blot, and immunohistochemistry. RESULTS Mosapride and high dose (4 g/kg) of aqueous FAI extracts significantly improved the bowel movement in cathartic colons compared to untreated model colons as measured by the intestinal transit rate (70.06 ± 7.25 and 72.02 ± 8.74, respectively, vs 64.12 ± 5.19; P < 0.05 for both). Compared to controls, the ultramicrostructure of cathartic colons showed signs of neural degeneration. Treatment with mosapride and aqueous FAI extracts resulted in recovery of ultrastructural pathology. Treatment with mosapride alone upregulated the gene and protein expression of 5-HTR4 compared to untreated controls (P < 0.05 for both). Treatment with aqueous FAI extracts (≥ 2 g/kg) increased 5-HTR4 mRNA levels (P < 0.05), but no change in protein level was observed by Western blot or immunohistochemistry. The mRNA and protein levels of neurofilament-H were significantly increased with mosapride and ≥ 2 g/kg aqueous FAI extracts compared to controls (P < 0.05 for all). CONCLUSION Aqueous FAI extracts and mosapride strengthen bowel movement in cathartic colons via increasing the expression of 5-HTR4 and neurofilament-H.
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Ahn TS, Kim DG, Hong NR, Park HS, Kim H, Ha KT, Jeon JH, So I, Kim BJ. Effects of Schisandra chinensis extract on gastrointestinal motility in mice. JOURNAL OF ETHNOPHARMACOLOGY 2015; 169:163-169. [PMID: 25862968 DOI: 10.1016/j.jep.2015.03.071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 03/02/2015] [Accepted: 03/13/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Schisandra chinensis (Turcz.) Baill. (SC) continues to be used as a traditional folk medicine in Asia, especially for the treatment of gastrointestinal (GI) disorders related to gastritis, diarrhea, enterocolitis and abnormal GI motility. AIM OF THE STUDY Because GI disorders, especially abnormal GI motility, are major lifelong problems, we investigated the effects of SC on the pacemaker activity of the interstitial cells of Cajal (ICCs) in murine small intestine and GI motility. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials generated by cultured ICCs. In vivo effects of SC on GI motility were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal and GI motility dysfunction mice. RESULTS SC extracts depolarized the membrane potentials of ICCs in a dose dependent manner. Pretreatment with Ca(2+) free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in the endoplasmic reticulum) abolished the generation of pacemaker potentials by ICCs, and under these conditions, SC extract did not depolarize the membrane potentials of ICCs. In addition, membrane depolarizations were inhibited by intracellular GDPβS and by U-73122 (an active phospholipase C (PLC) inhibitor). In normal mice, ITRs were significantly increased by SC extract (0.1-1g/kg, intragastrically (i.g.)) in a dose dependent manner. Also, SC extract significantly recovered the GI motility dysfunctions in acetic acid (AA)-injected and streptozotocin (STZ)-induced diabetic mice, which are the GI motility animal models. MATERIALS AND METHODS SC extract modulates pacemaker potentials in ICCs in a dose dependent manner via external and internal Ca(2+) regulations, and via G protein and the PLC pathway. In addition, SC extract increased ITRs in normal and abnormal GI motility mice models. This study shows that SC extract offers a basis for the development of a prokinetic agent that prevents or alleviates GI motility dysfunctions.
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Affiliation(s)
- Tae Seok Ahn
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Dae Geon Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Noo Ri Hong
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Hyun Soo Park
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Hyungwoo Kim
- Division of Pharmacology, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Ki-Tae Ha
- Division of Applied Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Ju-Hong Jeon
- Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Insuk So
- Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea.
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Hwang MW, Ahn TS, Hong NR, Jeong HS, Jung MH, Ha KT, Kim BJ. Effects of traditional Chinese herbal medicine San-Huang-Xie-Xin-Tang on gastrointestinal motility in mice. World J Gastroenterol 2015; 21:1117-1124. [PMID: 25632184 PMCID: PMC4306155 DOI: 10.3748/wjg.v21.i4.1117] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 08/05/2014] [Accepted: 09/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of San-Huang-Xie-Xin-Tang (SHXXT), a herbal product used in traditional Chinese medicine, on gastrointestinal (GI) motility in mice. METHODS The in vivo effects of SHXXT on GI motility were investigated by measuring the intestinal transit rates (ITRs) using Evans blue in normal mice and in mice with experimentally induced GI motility dysfunction (GMD). RESULTS In normal ICR mice, ITRs were significantly and dose-dependently increased by SHXXT (0.1-1 g/kg). GMD was induced by injecting acetic acid or streptozotocin intraperitoneally. The ITRs of GMD mice were significantly reduced compared to normal mice, and these reductions were significantly and dose-dependently inhibited by SHXXT (0.1-1 g/kg). CONCLUSION These results suggest that SHXXT is a novel candidate for the development of a prokinetic agent that may prevent or alleviate GMD.
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Hwang MW, Lee JH, Kim BJ. Carthami Flos Depolarizes the Interstitial Cells of Cajal and Increases the Motility in Gastrointestinal Tract. INT J PHARMACOL 2014; 10:248-257. [DOI: 10.3923/ijp.2014.248.257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Xiong YJ, Chen DP, Lv BC, Liu FF, Wang L, Lin Y. Characteristics of nobiletin-induced effects on jejunal contractility. Fitoterapia 2014; 94:1-9. [PMID: 24468189 DOI: 10.1016/j.fitote.2014.01.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 01/16/2014] [Accepted: 01/17/2014] [Indexed: 12/27/2022]
Abstract
Nobiletin, a citrus polymethoxylated flavone, exhibits multiple biological properties including anti-inflammatory, anti-carcinogenic, and anti-insulin resistance effects. The present study found that nobiletin exerted significant stimulatory effects on the contractility of isolated rat jejunal segments in all 6 different low contractile states, and meanwhile significant inhibitory effects in all 6 different high contractile states, showing characteristics of bidirectional regulation (BR). Nobiletin-exerted BR on jejunal contractility was abolished in the presence of c-kit receptor tyrosine kinase inhibitor imatinib or Ca(2+) channel blocker verapamil. In the presence of neuroxin tetrodotoxin, nobiletin only exerted stimulatory effects on jejunal contractility in both low and high contractile states. Hemicholinium-3 and atropine partially blocked nobiletin-exerted stimulatory effects on jejunal contractility in low-Ca(2+)-induced low contractile state. Phentolamine or propranolol or l-NG-nitro-arginine significantly blocked nobiletin-exerted inhibitory effects on jejunal contractility in high-Ca(2+)-induced high contractile state respectively. The effects of nobiletin on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin light chain phosphorylation extent were also bidirectional. In summary, nobiletin-exerted BR depends on the contractile states of rat jejunal segments. Nobiletin-exerted BR requires the enteric nervous system, interstitial cell of Cajal, Ca(2+), and myosin phosphorylation-related mechanisms.
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Affiliation(s)
- Yong-Jian Xiong
- College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Da-Peng Chen
- College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Bo-Chao Lv
- College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Fang-Fei Liu
- College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Li Wang
- College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Yuan Lin
- College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, PR China.
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Kim BJ, Kim HW, Lee GS, Choi S, Jun JY, So I, Kim SJ. Poncirus trifoliate fruit modulates pacemaker activity in interstitial cells of Cajal from the murine small intestine. JOURNAL OF ETHNOPHARMACOLOGY 2013; 149:668-675. [PMID: 23911946 DOI: 10.1016/j.jep.2013.07.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 07/02/2013] [Accepted: 07/11/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Poncirus fructus (PF) has been widely used as a traditional medicine in Eastern Asia, especially to ameliorate the symptoms of gastrointestinal (GI) disorders related to abnormal GI motility. AIM OF THE STUDY Poncirus fructus (PF), also known as Poncirus trifoliata (L.) Raf. (Rutaceae), is widely used as a traditional medicine in Eastern Asia mainly to ameliorate the symptoms of gastrointestinal (GI) disorders related to abnormal GI motility. In a previous study, a methanol extract of PF was found to have particularly potent gastroprokinetic effects. Interstitial cells of Cajal (ICCs) are pacemaker cells in the gastrointestinal tract, but the action mechanisms of PF extract in mouse small intestinal ICCs have not been investigated. Therefore, in the present study, we investigated the effects of a methanol extract of PF (MPF) in mouse small intestinal ICCs. In addition, we sought to identify the receptors involved. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from small intestines. The whole-cell patch-clamp configuration was used to record potentials (current clamp) from cultured ICCs. In addition, we analyzed intracellular Ca(2+) concentrations ([Ca(2+)]i). RESULTS MPF decreased the amplitudes of pacemaker potentials in ICCs, and depolarized resting membrane potentials in a concentration dependent manner. Y25130 (a 5-HT3 receptor antagonist) and RS39604 (a 5-HT4 receptor antagonist) blocked MPF-induced membrane depolarizations, whereas SB269970 (a 5-HT7 receptor antagonist) did not. Pretreatment with Na(+) or Ca(2+)-free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in endoplasmic reticulum) abolished the generation of pacemaker potentials and suppressed MPF-induced activity. [Ca(2+)]i analysis showed that MPF increased [Ca(2+)]i. Furthermore, treatments with PD 98059, SB203580, or JNK II inhibitor blocked MPF-induced membrane depolarizations in ICCs. CONCLUSION These results suggest that MPF modulates pacemaker potentials through 5-HT3 and 5-HT4 receptor-mediated pathways via external Na(+) and Ca(2+) influx, and via Ca(2+) release from internal stores in a mitogen-activated protein kinase dependent manner. The study shows MPF is a good candidate for the development of a gastroprokinetic agent. In view of the effects of MPF on ICCs, further research is required, particularly to identify the active compound(s) involved and to determine their action mechanisms.
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Affiliation(s)
- Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
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Jang Y, Kim SW, Oh J, Hong GS, Seo EK, Oh U, Shim WS. Ghrelin receptor is activated by naringin and naringenin, constituents of a prokinetic agent Poncirus fructus. JOURNAL OF ETHNOPHARMACOLOGY 2013; 148:459-465. [PMID: 23639361 DOI: 10.1016/j.jep.2013.04.039] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 03/18/2013] [Accepted: 04/18/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Poncirus fructus (PF), also known as a dried immature fruit of Poncirus trifoliata (L.) Raf. (Rutaceae), has long been traditionally used for the various gastrointestinal disorders in Eastern Asia. AIM OF STUDY The aqueous extract of PF (PF-W) has the strong prokinetic effect, yet the underlying mechanism is still elusive. The present study investigated whether PF-W has any effect on motilin receptor or ghrelin receptor, since these receptors enhance intestinal motility when activated. MATERIALS AND METHODS The effect of PF-W and its components on motilin or ghrelin receptor was determined by calcium imaging and whole-cell patch clamp methods. RESULTS PF-W activates the ghrelin receptor, but not the motilin receptor, resulting in a transient increase of intracellular calcium levels. Furthermore, among various constituents of PF, only naringin and naringenin evoked the intracellular calcium augmentation via the ghrelin receptor. Moreover, cortistatin-8 - a ghrelin receptor inhibitor - specifically blocked naringin- and naringenin-induced calcium increases. In addition, naringin and naringenin induced inward currents in ghrelin receptor-expressing cells under whole-cell patch clamp configuration. CONCLUSION PF-W activates the ghrelin receptor, and naringin and naringenin are key constituents responsible for the activation of ghrelin receptor. Therefore, the present study suggests that the ghrelin receptor is a molecular entity responsible for the strong prokinetic activity of PF-W.
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Affiliation(s)
- Yongwoo Jang
- College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
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Kim BJ, Lee GS, Kim HW. Involvement of transient receptor potential melastatin type 7 channels on Poncirus fructus-induced depolarizations of pacemaking activity in interstitial cells of Cajal from murine small intestine. Integr Med Res 2013; 2:62-69. [PMID: 28664056 PMCID: PMC5481676 DOI: 10.1016/j.imr.2013.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 04/10/2013] [Accepted: 04/10/2013] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Extracts of Poncirus trifoliata (L.) Raf. (Rutaceae; PT) are widely used as a traditional medicine in Eastern Asia, especially for the treatment of gastrointestinal (GI) disorders related to GI motility. Interstitial cells of Cajal (ICCs) are pacemakers in the GI tract, and transient receptor potential melastatin type 7 (TRPM7) channels and Ca2+ activated Cl- channels are candidate pacemaker channels. METHODS In the present study, the effects of a methanolic extract of the dried roots of PT on ICC pacemaking activity were examined using the whole-cell patch-clamp technique. RESULTS The methanolic extract of PT (PTE) was found to decrease the amplitudes of pacemaker potentials in ICC clusters and to depolarize the resting membrane potentials in a concentration-dependent manner. Intracellular GDP-β-S suppressed PTE-induced depolarizations, and pretreatment with a U-73122 (a phospholipase C inhibitor) or with 2-APB (an 1,4,5-inositol triphosphate receptor inhibitor) abolished this generation of pacemaker potentials and suppressed PTE-induced effects. The applications of flufenamic acid, niflumic acid, waixenicin A, or 5-lipoxygenase inhibitors (NDGA or AA861) abolished this generation of pacemaker potentials and inhibited PTE-induced membrane depolarization. Furthermore, PTE inhibited TRPM7 channels but did not affect Ca2+-activated Cl- channels (both channels play important roles in the modulation of the pacemaking activity related to GI motility). CONCLUSION These results suggest that the PTE-induced depolarization of pacemaking activity occurs in a G-protein-, phospholipase C-, and 1,4,5-inositol triphosphate-dependent manner via TRPM7 channels in cultured ICCs from murine small intestine, which indicates that ICCs are PTE targets and that their interactions affect intestinal motility.
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Affiliation(s)
- Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea
| | - Guem San Lee
- Wonkwang University College of Korean Medicine, Iksan, Korea
| | - Hyung Woo Kim
- Division of Pharmacology, Pusan National University School of Korean Medicine, Yangsan, Korea
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Lyu JH, Lee HT. Effects of dried Citrus unshiu peels on gastrointestinal motility in rodents. Arch Pharm Res 2013; 36:641-8. [PMID: 23463336 DOI: 10.1007/s12272-013-0080-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Accepted: 02/21/2013] [Indexed: 12/21/2022]
Abstract
Aqueous extracts of the dried mature (ANP-W) and immature Citrus unshiu peels (CUP-W) have been used as a traditional folk medicine for the treatment of gastrointestinal (GI) motility disorders in Korea. In the present study, neither ANP-W nor CUP-W exhibited significant toxicity even at an oral dose of 5 g/kg to mice. The effects of ANP-W and CUP-W on GI motor function were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal mice and rats with experimental GI motility dysfunctions (GMDs). In normal mice, the ITR was significantly increased by ANP-W (0.1-1 g/kg) in a dose dependent manner, whereas CUP-W elicited no significant change. GMD was induced by appropriate surgery or an intraperitoneal injection of acetic acid to the rats. The ITR in the GMD rats was significantly retarded compared to that in normal rats. However, the retardation was significantly inhibited by ANP-W (0.1-1 g/kg) in a dose dependent manner. The above results suggest that ANP-W has the potential for development as a prokinetic agent that may prevent or alleviate GMD in human patients.
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Affiliation(s)
- Ju Hyeong Lyu
- Department of Life Science and Biotechnology, College of Natural Sciences, Dong-eui University, Busan, 614-714, Korea
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Jang Y, Kim TK, Shim WS. Naringin Exhibits in vivo Prokinetic Activity via Activation of Ghrelin Receptor in Gastrointestinal Motility Dysfunction Rats. Pharmacology 2013; 92:191-7. [DOI: 10.1159/000354579] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 07/18/2013] [Indexed: 01/16/2023]
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Shim WS, Back H, Jung SW, Kim JW, Jang Y, Lee B, Seo EK, Oh U, Shim CK. An aqueous extract of Poncirus fructus activates the prokinetic activity of 5-HT receptor subtype 4 without hERG interaction. JOURNAL OF ETHNOPHARMACOLOGY 2010; 132:328-333. [PMID: 20736054 DOI: 10.1016/j.jep.2010.08.042] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Revised: 08/11/2010] [Accepted: 08/17/2010] [Indexed: 05/29/2023]
Abstract
AIM OF THE STUDY Poncirus fructus (PF)--also known as the dried, immature fruit of Poncirus trifoliata (L.) Raf. (Rutaceae)--is a natural substance that has long been used for various gastrointestinal disorders in eastern Asia. An aqueous extract of PF (PF-W) has particularly potent gastroprokinetic effects, but its molecular mechanism was not well understood. Identification of the underlying prokinetic mechanism of PF-W was pursued in the present study. MATERIALS AND METHODS Changes in in vitro cAMP levels and in vivo intestinal transit rate (ITR) caused by PF-W were measured after pretreatment with GR125487, an antagonist for serotonin receptor subtype 4 (5-HT4R). An [(3)H] astemizole binding assay and electrophysiology experiments were performed to determine if PF-W has any interaction with the human ether-à-go-go related gene (hERG) potassium channel. RESULTS PF-W induced an increase in intracellular cAMP in 5-HT4R-expressing HEK293T cells, indicating that PF-W does activate 5-HT4R. Moreover, pretreatment with GR125487 successfully blocked the increase, suggesting that the response was 5-HT4R-specific. More importantly, pretreatment of GR125487 in rats inhibited the elevation of ITR by PF-W, indicating that the prokinetic effect of PF-W was indeed exerted via 5-HT4R. On the other hand, both [(3)H]-astemizole binding assay and electrophysiological experiments revealed that PF-W did not interfere at all with the hERG channel. CONCLUSION It was found that PF-W exerts its prokinetic activity through a 5-HT4R-mediated pathway, with no interaction with hERG channels. Therefore, PF-W is a good candidate that might be developed as a prokinetic agent with fewer expected cardiac side effects.
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Affiliation(s)
- Won-Sik Shim
- National Research Laboratory for Transporters Targeted Drug Design & Research Institute of Pharmaceutical Sciences and Department of Pharmaceutics, College of Pharmacy, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul 151-742, Republic of Korea
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Wu D, Wang X, Zhou J, Yuan J, Cui B, An R, Hu Z. Traditional Chinese formula, lubricating gut pill, improves loperamide-induced rat constipation involved in enhance of Cl- secretion across distal colonic epithelium. JOURNAL OF ETHNOPHARMACOLOGY 2010; 130:347-353. [PMID: 20488235 DOI: 10.1016/j.jep.2010.05.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Revised: 04/28/2010] [Accepted: 05/08/2010] [Indexed: 05/29/2023]
Abstract
AIM OF THE STUDY Lubricating gut pill (LGP), a traditional Chinese formula, was widely used for the treatment of chronic constipation, especially in the elderly, in China. However, it is unclear whether LGP-induced laxative and/or lubricating effect is involved in water and electrolytes transport in distal colonic epithelium. MATERIALS AND METHODS The present study was designed to evaluate the effect of LGP on Cl(-) secretion across rat distal colonic epithelium mounted in Ussing chambers, and on a rat constipation model induced by loperamide, respectively. RESULTS Application of LGP in the apical side elicited a sustained increase in short circuit current (I(SC)) response in a concentration-dependent manner. Evidence that LGP-stimulated I(SC) was due to Cl(-) secretion is based on inhibition of current by (a) a Na(+)-K(+)-2Cl(-) cotransporter inhibitor bumetanide, (b) removal of Cl(-) ions in bath solution, and (c) the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel blocker DPC, suggesting that a apical cAMP-dependent Cl(-) channel was activated. LGP-stimulated I(SC) was also strongly inhibited by pretreatment with clotrimazole, indicating that the basolateral K(+) channel was also involved in maintaining this cAMP-dependent Cl(-) secretion. Pretreatment of tissues with indomethacin, but not atropine, tetrodotoxin or hexamethonium, inhibited LGP-induced response. In a rat constipation model, oral administration with LGP was significantly restored number of fecal pellets, water content and mucus secretion compared with loperamide-treated group alone. CONCLUSIONS LGP enhances Cl(-) secretion that is mostly mediated through the release of cyclooxygenase metabolites, by which provided an osmotic force for the subsequent laxative action observed in the rat constipation model.
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Affiliation(s)
- Dazheng Wu
- Institute of Chinese Materia Medica, Shanghai University of TCM, Shanghai, China
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Choi KH, Jeong SI, Hwang BS, Lee JH, Ryoo HK, Lee S, Choi BK, Jung KY. Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon. JOURNAL OF ETHNOPHARMACOLOGY 2010; 127:718-724. [PMID: 19963058 DOI: 10.1016/j.jep.2009.11.032] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Revised: 11/12/2009] [Accepted: 11/30/2009] [Indexed: 05/28/2023]
Abstract
AIM OF THE STUDY Poncirus trifoliata (L.) Raf. (Rutaceae, PT) has been commonly used for treating gastrointestinal (GI) disorders in Korean traditional medicine, but its pharmacological roles in the regulation of colonic motility have not been clarified. This study investigated the regulatory effects of PT on the colonic motility. MATERIALS AND METHODS Immature fruits of PT were sequentially partitioned with MeOH, n-hexane, CHCl(3), EtOAc, n-BuOH and H(2)O, and the effects of PT extracts on the contractility of colonic strips and colonic luminal transit in rats were measured in vitro and in vivo, respectively. RESULTS Among six different extracts, only hexane extract of PT (PTHE) dose-dependently increased the low frequency contraction of longitudinal muscle in distal colonic strips, and the ED(50) value was revealed to be 0.71 microg/ml. The contractile patterns induced by PTHE were remarkably different from those caused by acetylcholine (ACh) and serotonin (5-HT). The stimulatory effects of PTHE on the whole distal colonic strips were more prominent than on the mucosa/submucosa-denuded segments. The M(2) receptor-preferring, methoctramine (0.5 microM), and M(3) receptor-preferring antagonist, 4-DAMP (0.5 microM) significantly blocked the PTHE (1 microg/ml)-induced contraction of distal colon longitudinal muscles, whereas the 5-HT receptor antagonists (1.0 microM, alone or in combination) selective for 5-HT(3) (ondansetron), 5-HT(4) (GR113808) and 5-HT(1, 2, 5-7) (methysergide) receptors did not change the PTHE (1 microg/ml)-induced contractility of distal colon longitudinal muscles. SNAP (0.1mM), a NO donor, enhanced the stimulatory effects of PTHE on the longitudinal muscle of distal colon, but l-NAME (0.1mM), a NO synthesis inhibitor, had no effects. PTHE (10-100mg/kg) caused a dose-dependent increase of colonic luminal transit. CONCLUSIONS Collectively, these findings suggest that PTHE specifically acts on the longitudinal muscle of distal colon in rats, and these stimulatory effects are likely mediated, at least, by activation of acetylcholinergic M(2) and M(3) receptors.
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Affiliation(s)
- Keun Han Choi
- Department of Pharmacology, College of Medicine, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
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Shin EM, Zhou HY, Xu GH, Lee SH, Merfort I, Kim YS. Anti-inflammatory activity of hispidol A 25-methyl ether, a triterpenoid isolated from Ponciri Immaturus Fructus. Eur J Pharmacol 2010; 627:318-24. [DOI: 10.1016/j.ejphar.2009.10.036] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2009] [Revised: 09/26/2009] [Accepted: 10/14/2009] [Indexed: 11/29/2022]
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Shim WS, Back H, Seo EK, Lee HT, Shim CK. Long-term administration of an aqueous extract of dried, immature fruit of Poncirus trifoliata (L.) Raf. suppresses body weight gain in rats. JOURNAL OF ETHNOPHARMACOLOGY 2009; 126:294-299. [PMID: 19703543 DOI: 10.1016/j.jep.2009.08.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2009] [Revised: 08/11/2009] [Accepted: 08/15/2009] [Indexed: 05/28/2023]
Abstract
AIM OF STUDY The purpose of the present study was to examine the effects of daily administration of an aqueous extract of the dried, immature fruit of Poncirus trifoliata Raf. (Rutaceae) (PF-W) on body weight in rats. MATERIALS AND METHODS PF-W was used in following experiments: 10-week-long measurement of body weight and food intake, in vitro pancreatic lipase activity assay, in vivo triglyceride concentration study, and measurement of intestinal transit rate. RESULTS A high dose of PF-W (200 mg/2 mL/animal/day, in aqueous solution) was administered intragastrically to rats for 10 weeks. PF-W suppressed body weight gain by 6%. However, administration of PF-W at a lower dose (20 mg/animal/day) did not reduce weight gain. Administration of low- or high-dose PF-W had no effect on food intake throughout the experimental period. Additional experiments revealed that the suppressive effect of PF-W on body weight gain was not related to pancreatic lipase activity. Moreover, co-administration of PF-W with a lipid emulsion did not reduce plasma triglyceride concentration. Of interest, the high dose of PF-W significantly increased the rate of intestinal transit, whereas oral administration of the lower dose did not. Control and PF-W-treated groups did not differ in hematological and serum biochemical parameters, or in relative organ weights after 10 weeks of high-dose PF-W administration. CONCLUSION PF-W does not suppress body weight gain by interfering with fat absorption in a pancreatic lipase-dependent manner. The suppressive effect of PF-W on weight gain is likely due to the increased rate of intestinal transit, and the consequent reduction in nutrient absorption. Moreover, it appears that PF-W is relatively safe for long-term use. Taken together, the results of the present study suggest that long-term, daily administration of PF-W successfully suppressed body weight gain-apparently due to accelerated intestinal transit and not to interference with pancreatic lipase activity. Due to its apparent long-term safety, PF-W is a potential therapeutic agent for reduction of body weight in humans.
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Affiliation(s)
- Won-Sik Shim
- National Research Laboratory for Transporters Targeted Drug Design & Research Institute of Pharmaceutical Sciences, Department of Pharmaceutics, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 151-742, Republic of Korea
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Jayaprakasha GK, Mandadi KK, Poulose SM, Jadegoud Y, Nagana Gowda GA, Patil BS. Inhibition of colon cancer cell growth and antioxidant activity of bioactive compounds from Poncirus trifoliata (L.) Raf. Bioorg Med Chem 2007; 15:4923-32. [PMID: 17512744 DOI: 10.1016/j.bmc.2007.04.044] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2007] [Revised: 04/23/2007] [Accepted: 04/25/2007] [Indexed: 12/01/2022]
Abstract
Recently several plant derived natural compounds have been screened for their anticancer activity in order to identify putative compounds with novel structures or mechanism of action. In the present study, fruits of Poncirus trifoliata were extracted with acetone and loaded onto silica gel column chromatography. The column was eluted with different solvents to obtain two bioactive compounds. The purity of compounds was analyzed by HPLC and their structures were identified by 1H and 13C NMR experiments as beta-sitosterol and 2-hydroxy-1,2,3-propanetricarboxylic acid 2-methyl ester (HPCME). beta-Sitosterol, HPCME, and trolox were tested for their antioxidant capacity by oxygen radical absorbance capacity (ORAC) measurement. Further, these compounds were tested for their inhibition of cancer cell proliferation and apoptosis using human colon cancer cell line (HT-29). These results were compared with the corresponding activity on non-cancerous (COS-1 fibroblast) cells. Cell proliferation and induction of apoptosis were determined by MTT assay and nuclear staining. The MTT assay indicated that both the compounds exhibited differential inhibition at various concentrations. Significant arrest of cell growth was observed with beta-sitosterol even at low concentration such as 0.63 microM in 48 h and none of the compounds exerted any apparent cytostatic effects on the non-cancerous COS-1 fibroblast cells. Growth inhibition assay suggested the potential use of bioactive compounds as cancer chemopreventive and therapeutic agents. This is the first report on HPCME isolation and identification from Rutaceae family and beta-sitosterol from P. trifoliata.
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Affiliation(s)
- G K Jayaprakasha
- Vegetable & Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, TX 77843-2119, USA
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Han AR, Kim JB, Lee J, Nam JW, Lee IS, Shim CK, Lee KT, Seo EK. A New Flavanone Glycoside from the Dried Immature Fruits of Poncirus trifoliata. Chem Pharm Bull (Tokyo) 2007; 55:1270-3. [PMID: 17666859 DOI: 10.1248/cpb.55.1270] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A new flavanone glycoside, (2R)-5-hydroxy-4'-methoxyflavanone-7-O-{beta-glucopyranosyl-(1-->2)-beta-glucopyranoside} (1), was isolated from the EtOAc extract of dried immature fruit of Poncirus trifoliata, together with three known compounds, (2S)-poncirin (2), (2S)-naringin (3), and (2S)-poncirenin (4). The structure of compound 1 was elucidated by spectroscopic data analysis, including 1D and 2D NMR experiments. Among the isolates, compound 2 exhibited considerable inhibitory activity against lipopolysaccharide (LPS)-induced prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) production, and mRNA expression in RAW 264.7 murine macrophage cells.
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Affiliation(s)
- Ah-Reum Han
- College of Pharmacy and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea
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