查找使用阿拉丁产品的科研文献

Anxiolytic effects of corilagin by targeting Htr2c through activation of the TrkB/CREB/BDNF pathway

Xiaoyun Yun,Jianhui Wu,Jie Zhou,Linlin Song,Yongpei Tang,Hanghong Lo,Jerome P.L. Ng,Menghan Liu,Zhikang Wang,Liqun Qu,Huimiao Wang,Ruilong Zhang,Cairen Wang,Linna Wang,Jiujie Yang,Sookja Kim Chung,Vincent Kam Wai Wong,Betty Yuen Kwan Law

Background Anxiety disorders rank among the most ubiquitous neuropsychiatric disease classifications. Despite their substantial disease burden, the persistent lack of innovative, mechanistically grounded therapeutic interventions over the past two decades highlights an urgent need for novel pharmacological strategies. Purpose The aim of this study is to investigate the neuroprotective and anxiolytic effects of corilagin derived from plant sources, offering novel perspectives for the development of therapeutic strategies targeting anxiety disorders. Methods In this study, high-performance liquid chromatography-mass spectrometry analysis was performed on the crude extract of Phyllanthus emblica Linn. A glutamine-induced cell model and a scopolamine-induced anxiety model were established for in vitro and in vivo investigations, respectively. Anxiety-like behaviors were evaluated using Y-maze, open field tests, and fear conditioning experiments. Laser speckle contrast imaging was employed for relative and qualitative assessment of cerebral blood flow and perfusion in mice. Western blotting, quantitative real-time PCR, and flow cytometry were utilized to elucidate the underlying pathway mechanisms. Finally, RNA sequencing and recombinant adeno-associated virus (AAV)-mediated gene silencing experiments were conducted for target prediction and validation. Results Phyllanthus emblica Linn. derived corilagin showed a strong antioxidant activity in a glutamate-induced cell model. It also inhibited neuronal cell apoptosis caused by oxidative damage, rescued apoptosis from the late stage to the early stage and restored cellular viability. Corilagin alleviated anxiety as reflected by the improvement in scopolamine-induced mice’s behavior such as hyperlocomotion, working memory and emotion memory damage. By applying recombinant AAV-mediated Htr2c silencing shRNA, our findings indicate that corilagin targets the serotonergic system, producing anxiolytic effects by modulating Htr2c to influence 5-HT levels and activate the TrkB/CREB/BDNF pathway in the prefrontal cortex. Compared with the existing fluoxetine anxiolytic drug, this compound demonstrates unique liver-protective properties by downregulating the ALT and AST level. Conclusion This study revealed that corilagin, a bioactive hydrolysable tannin isolated from natural plants, has multiple efficacy in mitigating oxidative and apoptotic damage, alleviating anxiety. The superiority of corilagin as an Htr2c agonist lies in its lower risk of side effects, representing its potential as a novel therapeutic candidate through Htr2c-BDNF signaling modulation, offering a mechanistically innovative approach for both the prevention and clinical management of anxiety disorders.

Property-Based Design of Xanthine Derivatives as Potent and Orally Available TRPC4/5 Inhibitors for Depression and Anxiety

Zhaoxiang Song,Huaduan Liang,Chu Xue,Shuxian Wang,Younan Ren,Zhuang Zhang,Tifei Xu,Bo Niu,Mengmeng Song,Mengru Liu,Xu Qin,Jie Li,Xianya Zhao,Fang Zhao,Jianhua Shen,Zhengyu Cao,Kai Wang

Transient receptor potential canonical channels 4 and 5 (TRPC4/5) are nonselective cation channels involved in emotional regulation, positioning them to be promising targets for treating mental disorders such as anxiety and depression. HC-070, a potent TRPC4/5 inhibitor, exhibits significant anxiolytic and antidepressant effects in animal models, though its drug-like properties require optimization. In this study, we applied a property-based drug design (PBDD) approach to optimize HC-070, leading to the discovery of compound 32, which shows improved LipE and Fsp3 values, reduced hERG blocking activity, enhanced metabolic stability, increased aqueous solubility, and superior oral bioavailability. Oral administration of compound 32 in mouse models demonstrates anxiolytic and antidepressant efficacy comparable to fluoxetine. This study supports the therapeutic potential of TRPC4/5 inhibitors for mental disorders and identifies compound 32 as a promising candidate for further investigation. Furthermore, our work underscores the value of PBDD in optimizing lead compounds during drug discovery process.

Involvement of the dopamine D1 receptor system in the anxiolytic effect of cedrol in the elevated plus maze and light–dark box tests

Kai Zhang,Jing Lu,Lei Yao

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light–dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT 1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D 1 receptor antagonist) or sulpiride (dopamine D 2 /D 3 receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D 1 receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.

Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics

Xiaomin Yuan,Biqing Chen,Zhenglan Duan,Ziqian Xia,Yang Ding,Tuo Chen,Huize Liu,Baosheng Wang,Bolin Yang,Xiaoyong Wang,Shijia Liu,Jin-Yong Zhou,Yajun Liu,Qiong Wang,Zhaofeng Shen,Jun Xiao,Hongtao Shang,Weiwei Liu,Guoping Shi,Lei Zhu,Yugen Chen

Pleasant Odor Decreases Mouse Anxiety-like Behaviors by Regulating Hippocampal Endocannabinoid Signaling

Jia-Rui Bi,Hai-Wei Zha,Qing-Lin Gao,Hui Wu,Zhen-Jiang Liu,Dong Sun

Anxiety disorder is one of the most common neuropsychiatric disorders, and affects many people’s daily activities. Although the pathogenesis and treatments of anxiety disorder have been studied for several decades, the underlying mechanisms remain elusive. Here, we provide evidence that olfactory stimuli with inhaled linalool or 2-phenylethanol decreased mouse anxiety-like behaviors and increased the activities of hippocampal dentate granule cells (DGCs). RNA-sequencing analysis identified retrograde endocannabinoid signaling, which is a critical pathway for mood regulation and neuron activation, is altered in the hippocampus of both linalool- and 2-phenylethanol-exposed mice. Further studies found that selective inhibition of endocannabinoid signaling by injecting rimonabant abolished the activation of DGCs and the anxiolytic effect induced by linalool or 2-phenylethanol. Together, these results uncovered a novel mechanism by which linalool or 2-phenylethanol decreases mouse anxiety-like behaviors and increases DG activity likely through activating hippocampal retrograde endocannabinoid signaling.

Design, synthesis and pharmacological evaluation of triazolopyrimidines derivatives as novel agonists for benzodiazepine receptor

Mengjiao Li,Lina Hu,Shijia Yi,Hui Yan,Zheng Liu,Kang Lei,Xuekun Wang,Shiben Wang

In this paper, two series of triazolopyrimidines derivatives were designed, synthesized, and all the target compounds were structurally confirmed using 1 H NMR, 13 C NMR and HRMS methods. Pharmacological experiments were carried out using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and rotating rod (ROT) models for activity and neurotoxicity screening, and potential compounds were screened out for further determination of ED 50 , TD 50 and in vitro binding experiments. Finally, compound 5,7-Bis(pentyloxy)-[1,2,4]triazolo[1,5-a]pyrimidine ( 6b ) with best activity and lowest toxicity was obtained. The pharmacological results showed that the ED 50 of compound 6b was MES = 11.3 mg/kg, PTZ = 9.5 mg/kg, which was superior to that of the carbamazepine (MES = 6.3 mg/kg) and ethosuximide (PTZ = 3.6 mg/kg). The IC 50 of compound 6b binding affinity toward the GABA A receptor was 0.15 µM, and the GABA content experiments showed that compound 6b significantly increased the GABA content in the rat brain. In elevated plus maze (EPM) assay, compound 6b possessed anxiolytic effects. In silico studies, most of the target compounds have suitable physicochemical and pharmacokinetic data with the possibility of drug-forming properties, molecular docking results showed that compound 6b could generate more interactions with the amino acid residues of diazepam active site of GABA A receptor.

Self-assembling modified neuropeptide S enhances nose-to-brain penetration and exerts a prolonged anxiolytic-like effect

Shu Li,Chen Guo,Xingjiao Zhang,Xiaojing Liu,Jing Mu,Chunxia Liu,Yali Peng,Min Chang

Anxiety disorders are the most common mental diseases and can greatly disrupt everyday life. Although there has been substantial research on anxiety disorders, novel therapeutics are needed. Neuropeptide S (NPS) is a potential therapeutic candidate owing to its strong anxiolytic activity; however, some disadvantages, such as its poor metabolic stability and inability to cross the blood–brain barrier (BBB), limit its use in the clinic. Herein, inspired by nose-to-brain drug delivery strategies, an endogenous 20-amino-acid-long mNPS peptide was modified by incorporating palmitic acid into its functional Lys12 side chain (M-3), which was expected to facilitate nose-to-brain penetration and exert a prolonged anxiolytic-like effect compared to mNPS. We found that M-3 assembled into nanofibers that retained the bioactivity of NPS and exhibited obvious improvements in metabolic stability. Notably, as expected, self-assembled M-3 was able to penetrate into the brain and exert anxiolytic effects. The elevated plus-maze (EPM) results further revealed that M-3 could produce prolonged anxiolytic-like effects in mice. In vivo imaging studies revealed that self-assembled M-3 could be efficiently transported from the nasal cavity to the brain. Furthermore, when intranasally administered, this molecule exhibited a significantly prolonged anxiolytic-like effect, which further illustrated that this molecule has a potent nose-to-brain penetration in vivo. Overall, this self-assembled nanofiber showed potent nose-to-brain penetration ability and prolonged bioactivity.

Wheel-Running Exercise Alleviates Anxiety-Like Behavior via Down-Regulating S-Nitrosylation of Gephyrin in the Basolateral Amygdala of Male Rats

Ping-Fen Yang,Tai-Lei Nie,Xia-Nan Sun,Lan-Xin Xu,Cong Ma,Fang Wang,Li-Hong Long,Jian-Guo Chen

Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S-nitrosylation of gephyrin (SNO-gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO-gephyrin is significantly increased in the BLA of high-anxiety rats and a downregulation of SNO-gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO-gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABA A R γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic-like effects of physical exercise. This study reveals a key role of downregulating SNO-gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post-translational modifications in the brain after exercise.