ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Chen Yu-qi,Ye Jun-rui,Wang Sha-sha,Peng Ye,Zhou Run,Yuan Ruo-lan,Wang Wen-fei,Chu Shi-feng,Zhang Zhao,Chen Nai-hong
Selective serotonin reuptake inhibitors (SSRIs) are characterized by delayed therapeutic onset largely due to their reliance on the desensitization of 5-HT 1A autoreceptors (5-HT 1A R auto s) within the dorsal raphe nucleus (DRN). It has been shown that dissociation of serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) interaction selectively modulates 5-HT 1A R auto s, thereby facilitating fast-onset antidepressant responses. Targeting the atypical disk large/ZO-1 (PDZ) domain has been implicated in the SERT-nNOS interaction. In this study, we established a drug screening system based on mBRET combined with biological tests to find SERT-nNOS interaction blockers (SNIBs). During screening the compound libraries, 9 top candidates were found to be capable of binding to the PDZ domain of nNOS. We then identified esflurbiprofen as a promising fast-onset antidepressant candidate. Pharmacodynamic studies revealed that esflurbiprofen effectively penetrated the DRN following systemic administration. Esflurbiprofen (10, 20, 40 mg/kg, i.p., once every 4 days) dose-dependently ameliorated depressive-like behaviors in mice subjected to chronic social defeat stress (CSDS) and chronic restraint stress (CRS). In rs-fMRI analysis, we found that esflurbiprofen enhanced the functional connectivity of emotion-related neural networks in CSDS mice. We further demonstrated that esflurbiprofen disrupted the SERT-nNOS complex in the DRN, augmented membrane-associated SERT, and reduced the concentration of 5-HT in the extracellular space of the DRN. This cascade subsequently enhanced serotonergic neuronal firing through the inhibition of negative feedback mediated by 5-HT 1A R auto s, culminating in an augmented release of 5-HT from serotonergic neurons projecting to the prefrontal cortex and hippocampus. These results highlight the potential of esflurbiprofen to induce rapid antidepressant effects by targeting the SERT-nNOS interaction within the DRN.
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高影响因子
NUCLEAR MEDICINE AND BIOLOGY
·
2024
·
IF 3.6
Yuli Sun,Guangwen Li,Haiyan Hong,Lin Zhu,Hank F. Kung,Yan Zhang,Jinxia Zhu
Objective Diabetes mellitus (DM) is one of the major diseases in the world. Nuclear medicine imaging may be able to detect functional status of pancreatic β cells in vivo , which might elucidate the pathological mechanisms of diabetes and develop individualized treatment plans. In this study, we evaluated the ability of [ 125 I]ADAM, a serotonin transporter (SERT) imaging agent, as a probe for detecting pancreatic β-cell mass (BCM). Methods In vitro cell studies were evaluated in INS-1 cells (rat islet β cell line). Biodistribution studies were performed in male normal Sprague-Dawley rats and alloxan-induced type 1 diabetes mellitus (T1DM) rats. Distribution and expression of SERT protein in pancreas of rats were also measured by immunofluorescence staining and Western blot. Results In vitro cell studies showed that the concentration of [ 125 I]ADAM associated with the INS-1 cells was increased gradually with incubation time, and the SERT specific inhibitor, escitalopram, exhibited the inhibitory effect on this interaction. Biodistribution studies also showed that the uptake of [ 125 I]ADAM in the pancreas of normal rats was decreased in the presence of escitalopram. However, in the T1DM rat model with a significant β cells reduction, the uptake of pancreas was increased when compared with the control. Through immunofluorescence staining and Western blot, it was found that both the endocrine and exocrine cells of the normal pancreas expressed SERT protein, and the level of SERT protein in the exocrine cells was higher than islets. In the diabetic state, the expression of SERT in the exocrine cells was further increased. Conclusions The SERT imaging agent, [ 125 I]ADAM, at the present form will not be suitable for imaging β cells, specifically because there were extraordinarily high non-specific signals contributing from the exocrine cells of pancreas. In addition, we noticed that the level of SERT expression was abnormally elevated in the diabetic state, which might provide an unexpected target for studying the pathological mechanisms of diabetes.
研究领域:
医学影像学
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内分泌学
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糖尿病研究
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 5
·2119
·
IF 4.9
Chengwei Wang,Chunjie Wu,Linjiang Song
Saiga antelope horn (SAH), a rare traditional Chinese medicine, exhibits activities of anti-feverish convulsions and anti-inflammation, whereas its underlying mechanism and specific pharmacological components are still unclear. In the present study, transient receptor potential ankyrin 1 (TRPA1), a major transient receptor potential cation channel was used as a target protein to identified TRPA1 high-affinity peptides (THPs) from SAH digests. Firstly, the SAH was digested under in vitro gastrointestinal conditions. With the method of affinity ultrafiltration and liquid chromatography–mass spectrometry (AUF-LC/MS), about 200 peptides that have a high-affinity interaction with the TRPA1 protein were screened from SAH digests. Subsequently, bioactivity databases and molecular docking were further exploited to identified three THPs, including RCWPDCR, FGFDGDF, and WFCEGSF. Furthermore, RIN-14B cells, characterized by the high expression of TRPA1 on cell surfaces, were used as the cell model to investigate the biological effect of THPs. Immunofluorescence and ELISA were conducted and showed that THPs can increase the intracellular Ca2+concentration and serotonin (5-HT) secretion in RIN-14B cells by activating TRPA1, which is evidenced by impaired upregulation of intracellular Ca2+levels and 5-HT secretion after pretreatment with the TRPA1 inhibitor (HC-030031). Moreover, an analysis of Western blots displayed that THPs up-regulated the expression levels of the 5-HT synthesis rate-limiting enzyme (TPH1) and 5-hydroxytryptophan decarboxylase (Ddc), while serotonin reuptake transporter (SERT) levels were down-regulated, suggesting that THPs enhance 5-HT secretion by regulating the 5-HT synthesis pathway. In summary, our findings demonstrate that THPs, which were identified from SAH digest via TRPA1-targeted affinity panning, exhibited the activation of the TRPA1 channel and enhanced 5-HT release in RIN-14B cells.
研究领域:
药理学
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分子生物学
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传统中药
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细胞生物学
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高影响因子
NEUROGASTROENTEROLOGY AND MOTILITY
·
2021
·Vol. 33
·期 12
·e14196
·
IF 3.598
Youyou Lu,Junxue Zhang,Xiaohong Zhou,Meiyu Guan,Zhe Zhang,Xi Liang,Lingjun Tong,Huaxi Yi,Pimin Gong,Lu Bai,Hui Zhou,Tongjie Liu,Lanwei Zhang
Background Constipation is a gastrointestinal symptom with high incidence rate and large number of patients. It is becoming one of the urgent medical problems. Poor intestinal motility is one of the important causes of constipation. Current drug treatments for constipation are associated with many side effects; thus, it is necessary to study more effective treatment methods and potential mechanism. Methods A zebrafish model of intestinal motility obstruction was established by loperamide hydrochloride to evaluate the effect of probiotic, food ingredients, and combination on intestinal peristalsis according to intestinal peristalsis frequency counts. The gastrointestinal survival ability of the best probiotics was evaluated by surface hydrophobicity, self-aggregation, acid and bile salt tolerance, and gastrointestinal transit tolerance. Interactions between probiotics and food ingredients were studied in vivo and in vitro. The expression of 5-HT was detected by ELISA and fluorescence immunoassay, and 5-HT related genes were detected by RT-PCR. Key Results We obtained the probiotics, food ingredients, and combination that effectively promoted intestinal peristalsis, X11 and YRL577, P . persica and KGM, KGM + X11, respectively. Both KGM and P . persica promoted colonization of probiotics in vivo. KGM + X11 could effectively promote the increase in 5-HT synthesis in zebrafish via up-regulating gene expression of TPH-1, TPH-2, and 5-HT R and down-regulating gene expression of SERT. The specific in-depth mechanism needs further study. Conclusions and Inferences The combinations of KGM with X11 effectively promoted intestinal peristalsis. We provide a theoretical basis for new modalities that can promote intestinal peristalsis and alleviate constipation.
研究领域:
胃肠病学
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药理学
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微生物学
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营养学
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高影响因子
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