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Morinda officinalis oligosaccharides increase serotonin in the brain and ameliorate depression via promoting 5-hydroxytryptophan production in the gut microbiota

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3298-3312页

作者： Zheng-Wei Zhang Chun-Sheng Gao Heng Zhang Jian Yang Ya-Ping Wang Li-Bin Pan Hang Yu Chi-Yu He Hai-Bin Luo Zhen-Xiong Zhao Xin-Bo Zhou Yu-Li Wang Jie Fu Pei Han Yu-Hui Dong Gang Wang Song Li Yan Wang Jian-Dong Jiang Wu Zhong State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences/Peking Union Medical CollegeBeijing 100050China Beijing Institute of Pharmacology and Toxicology Beijing 100000China Beijing Synchrotron Radiation Facility Institute of High Energy PhysicsChinese Academy of SciencesBeijing 100049China The National Clinical Research Center for Mental Disorders&Beijing Key Laboratory of Mental Disorders Beijing Anding HospitalCapital Medical UniversityBeijing 100088China Advanced Innovation Center for Human Brain Protection Capital Medical UniversityBeijing 100069China School of Pharmaceutical Sciences Hainan UniversityHainan 570228China National Engineering Research Center for the Emergence Drugs Beijing 100000China

Morinda officinalis oligosaccharides(MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan → 5-hydroxytryptophan(5-HTP) → serotonin(5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan;meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation,and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood-brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide,as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota.

关键词： Depression Morinda oficinalis oligosaccharides Gut microbiota Tryptophan hydroxylase 5-hydroxytryptophan decarboxylase 5-hydroxytryptophan Serotonin Drug metabolism

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Evaluation of necrosis avidity of radioiodinated 5-hydroxytryptophan and its potential applications in myocardial infarction imaging

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Chinese Chemical Letters 2019年第1期30卷 83-86页

作者： Lin Ma Lingqiao Cai Qiaomei Jin Jiajia Liang Dongjian Zhang Wei Liu Yicheng Ni Zhiqi Yin Jian Zhang Ke Pan Department of Natural Medicinal Chemistry & Department of TCMs Pharmaceuticals School of Traditional Chinese Pharmacy China Pharmaceutical University Affliated Hospital of Integrated Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Laboratories of Translational Medicine Jiangsu Province Academy of Traditional Chinese Medicine College of Pharmacy Nanjing University of Chinese Medicine Department of Nuclear Medicine The First Affiliated Hospital of Nanjing Medical University Theragnostic Laboratory Campus Gasthuisberg

This study aimed to seek necrosis avid agents with high safety from DNA binding agents. The interaction of 5-hydroxytryptophan(5-HTP) with DNA was investigated by a series of spectroscopic studies. Then, 5-HTP was labeled with iodine-131([^(131)I]5-HTP) and the necrosis avidity of [^(131)I]5-HTP was evaluated by in vitro cell binding assays, in vivo biodistribution experiments and blocking experiment. Finally, the potential of [^(131)I]5-HTP to image necrotic myocardium was explored in rat models with myocardial infarction by SPECT/CT imaging. Results showed that 5-HTP bound to DNA in groove binding mode and the binding constant was 1.69×10~4 L/mol. [~(^(131))I]5-HTP showed specific affinity to necrotic A549 cells,which might be related to cell nucleus. Biodistribution and autoradiography results showed preferential accumulation of [^(131)I]5-HTP in necrotic muscle(necrotic/viable muscle ratio: 6.95 ? 0.68 at 3 h postinjection(p.i.)), which could be blocked by 5-HTP with 66.7% decline, indicating that [^(131)I]5-HTP might share the same necrotic targets with 5-HTP. On SPECT/CT images, a hotspot was clearly observed at 3h *** the necrotic myocardium while not in the control myocardium. In conclusion, [^(131) I]5-HTP is a novel necrosis avid agent and can rapidly visualize necrotic myocardium at 3 h p.i. The necrosis avidity mechanism of [^(131) I]5-HTP may be attributed to its interactions with exposed DNA in the necrotic tissues.

关键词： Radioiodinated 5-hydroxytryptophan Necrosis avidity DNA Groove binding Necrotic myocardium imaging

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Comparison of 5-hydroxytryptophan signaling pathway characteristics in diarrhea-predominant irritable bowel syndrome and ulcerative colitis

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World Journal of Gastroenterology 2016年第12期22卷 3451-3459页

作者： Feng-Yan Yu Shao-Gang Huang Hai-Yan Zhang Hua Ye Hong-Gang Chi Ying Zou Ru-Xi Lv Xue-Bao Zheng Traditional Chinese Medicine Institute Guangdong Medical University Dongguan 524023 Guangdong Province China University City Branch Hospital of Guangdong Provincial Hospital of Traditional Chinese Medicine Guangzhou 510006 Guangdong Province China Guangdong Key Laboratory of Natural Medicine Research and Development Guangdong Medical College Zhanjiang 524023 Guangdong Province China

AIM: To study differences in the visceral sensitivity of the colonic mucosa between patients with diarrheapredominant irritable bowel syndrome(IBS-D) and those with ulcerative colitis(UC) in remission and to relate these differences with changes in the 5-hydroxytryptophan(5-HT) signaling pathway. METHODS: Gastrointestinal symptoms were used to determine the clinical symptom scores and rectal visceral sensitivity of patients with IBS-D and patients with UC in remission. Blood levels of 5-HT and5-hydroxyindoleacetic acid(5-HIAA) were measured using an HPLC-electrochemical detection system. The levels of 5-HT 3 receptor(3R), 4R, and 7R m RNAs in colonic biopsy samples were detected using reverse transcription-polymerase chain reaction. The protein expression of TPH1 was analyzed by Western blot and ***: Abdominal pain or discomfort, stool frequency, and the scores of these symptoms in combination with gastrointestinal symptoms were higher in the IBS-D and UC groups than in the control groups. However, no significant differences were observed between the IBS-D and UC remission groups. With respect to rectal visceral sensitivity, the UC remission and IBS-D groups showed a decrease in the initial perception threshold, defecating threshold and pain threshold. However, these groups exhibited significantly increased anorectal relaxation pressure. Tests examining the main indicators of the 5-HT signaling pathway showed that the plasma 5-HT levels, 5-HIAA concentrations, TPH1 expression in the colonic mucosa, and 5-HT3 R and 5-HT5 R expression were increased in both the IBS-D and the UC remission groups; no increases were observed with respect to 5-HT7 R ***: The IBS-D and UC groups showed similar clinical symptom scores, visceral sensitivity, and levels of serotonin signaling pathway indicators in the plasma and colonic mucosa. However, the pain threshold and 5-HT7 R expression in the colonic mucosa were significantly different betwe

关键词： Stomach type diarrhea Diarrhea-predominant irritable bowel syndrome Ulcerative colitis in remission 5-hydroxytryptophan

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Effects of 5-hydroxytryptophan on morphine-induced sensitization in mice

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Journal of Chinese Pharmaceutical Sciences 2008年第1期17卷 1-5页

作者：李俊旭陈素清邓艳萍梁建辉北京大学中国药物依赖性研究所神经药理学研究室北京100083

To investigate the involvement of central serotonergic system in behavioral sensitization to morphine in mice. Male Kunming mice were treated （i.p.） with saline or morphine 10 mg/kg twice daily for 3 d and then drug manipulation was suspended for 5 d. On day 9, a challenge dose of morphine （10 mg/kg） was given and the locomotor activity was measured for 60 rain to confkrm the establishment of behavioral sensitization in mice. Moreover, 5-hydroxytryptophan （5-HTP）, a precursor of serotonin, at the doses of 20-80 mg/kg was given i.p. in combination with daily morphine treatment （induction）, during the morphine treatment suspension （transfer） or prior to the challenge dose of morphine （expression） and locomotor activity was measured on day 9 after the challenge dose of morphine. Twice daily of morphine injection induced robust behavioral sensitization in mice as evidenced by significantly higher locomotion on day 9 for multiple treatment with morphine than saline in mice. 5-HTP treatment selec- tively and dose-dependently blocked the induction, but not the transfer nor the expression of morphine induced behavioral sensitization. This study provides clear evidence that up-regulation of central serotonergic system may suppress the induction of morphine sensitization in mice.

关键词： 5-hydroxytryptophan Morphine Behavioral sensitization Mice

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L-type calcium channel blockers enhance 5-HTP-induced antinociception in mice

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Acta Pharmacologica Sinica 2004年第5期25卷 102-108页

作者： Jian-hui LIANG1, Jun-xu LI, Xu-hua WANG, Bi CHEN, Ying LU, Pan ZHANG, Rong HAN, Xiang-feng YEDepartment of Neuropharmacology, National Institute on Drug Dependence, Peking University, Beijing 100083, China 北京大学中国药物依赖性研究所北京 100083

AIM: To investigate the involvement of L-type Ca2+ channels in antinociceptive action induced by the 5-HT precursor,5-hydroxytryptophan (5-HTP). METHODS: Female Kunming mice were treated with either 5-HTP (20-80 mg/kg,ip) alone, or the combination of 5-HTP and fluoxetine (2-8 mg/kg, ip), pargyline (15-60 mg/kg, ip), nimodipine (2.5-10 mg/kg, ip), nifedipine (2.5-10 mg/kg, ip), verapamil (2.5-10 mg/kg, ip), CaCl2 (5-20 mmol/L, icv), or EGTA(0.5-3 mmol/L, icv) prior to the hot-plate test (55 C, hind-paw licking latency). In addition, locomotor activity inmice treated with 5-HTP alone was measured using an ambulometer with five activity boxes. RESULTS: Ipinjection of 5-HTP alone had no influence on the spontaneous locomotor activity, whereas dose-dependently in-creased the latency to licking hind-paw in the hot-plate test in mice. The inhibitory effects of 5-HTP on nociceptiveresponse were significantly enhanced by fluoxetine in the mouse hot-plate test. At a sub-effective dose, pargylinecould cause a leftward shift in the dose-response curve of 5-HTP-induced antinociception. Co-administration with5-HTP and nimodipine, nifedipine, or verapamil obviously potentiated the antinociceptive effects elicited by ***, 5-HTP-induced antinociception was antagonized by CaCl2 and enhanced by EGTA injected icv in themouse hot-plate test. CONCLUSION: These findings suggest that systemic administration of 5-HTP may yield theantinociceptive effects, which are related to Ca2+ influx from extracellular fluid through L-type Ca2+ channels.

关键词： serotonin 5-hydroxytryptophan fluoxetine pargyline calcium channel blockers pain measure-ment

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Analgesis and Wound Healing Effect of Chitosan and Carboxymethyl Chitosan on Scalded Rats

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Journal of Ocean University of China 2014年第5期13卷 837-841页

作者： HUANG Shuya HAN Baoqin SHAO Kai YU Miao LIU Wanshun College of Marine Life Sciences Ocean University of China

Analgesis and wound healing effect of chitosan and carboxymethyl chitosan on scalded rats were investigated. A II degree scald model was established in rats, which was subsequently treated with chitosan and carboxymethyl chitosan solution, respectively. The concentration of bradykinin and 5-hydroxytryptophan was detected by assaying enzyme-linked immunosorbent. Healing condition was observed and pathological sections were made to determine the healing effect of chitosan and carboxymethyl chitosan. Results showed that the concentration of bradykinin and 5-hydroxytryptophan peaked at the third hour post-wound in all groups, while the concentration of hydroxyproline peaked at the seventh day post-wound in both chitosan and carboxymethyl chitosan group. The concentration of bradykinin and 5-hydroxytryptophan of carboxymethyl chitosan group was significantly lower than that of control(P 5), while that of chitosan group was similar to that of control(P > 0.05). These findings indicated that carboxymethyl chitosan reduced the concentration of algogenic substances, resulting in analgesia. During the whole recovery process, the hydroxyproline concentration in chitosan and carboxymethyl chitosan group on day 3 and 7 was significantly higher than that of control(P 5). These findings indicated that chitosan and carboxymethyl chitosan accelerated tissue repair. Meanwhile, chitosan performed better in healing than carboxymethyl chitosan in both decrustation and healing time. In conclusion, carboxymethyl chitosan showed significant analgesis and wound-healing promotion effect, but chitosan only showed wound-healing promotion effect.

关键词： bradykinin 5-hydroxytryptophan hydroxyproline carboxymethyl chitosan

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