Targeting the Hedgehog pathway with novel Gli1 hydrophobic tagging degraders.

The Hedgehog/Glioma-associated oncogene (Hh/Gli) signaling pathway plays an essential role in embryonic development and tissue homeostasis. Aberrant regulation of this pathway has been linked to various human malignancies. Gli1, the downstream transcription factor of the Hh pathway, is the ultimate effector of the canonical Hh pathway and has been identified as a common regulator of several tumorigenic pathways prevalent in Hh-independent cancers. Thus Gli1 represents a unique and promising drug target for a wide range of cancers. However, the identification and development of small molecules that directly target Gli1 protein have progressed slowly, due to an insufficient efficacy and selectivity. Herein, we developed novel small-molecule Gli1 degraders based on the hydrophobic tagging (HyT) strategy. The Gli1 HyT degrader 8e potently inhibited the proliferation of Gli1-overexpressed HT29 colorectal cancer cells, induced Gli1 degradation with a DC50 value of 5.4 µM in HT29 and achieved 70% degradation at 7.5 µM in MEFPTCH1-/- and MEFSUFU-/-cell lines, via proteasome pathway. Compared to the canonical Hh antagonist Vismodegib, 8e exhibited much stronger potency in suppressing the mRNA expression of Hh target genes in Hh-overactivated MEFPTCH1-/- and Vismodegib resistant MEFSUFU-/- cells. Our study provides small molecule Gli1 degraders effectively interfering with both canonical and noncanonical Hh signaling and overcoming current Smoothened (SMO) antagonists resistance, which might pave a new avenue for developing therapeutic modalities targeting Hh/Gli1 signaling pathway.

Discovery of orally effective and safe GPR40 agonists by incorporating a chiral, rigid and polar sulfoxide into ß-position to the carboxylic acid.

GPR40 is primarily expressed in pancreatic islet ß-cells, and its activation by endogenous ligands of medium to long-chain free fatty acids or synthetic agonists is clinically proved to improve glycemic control by stimulating glucose-dependent insulin secretion. However, most of the reported agonists are highly lipophilic, which might cause lipotoxicity and the off-target effects in CNS. Particularly, the withdrawal of TAK-875 from clinical trials phase III due to liver toxicity concern threw doubt over the long-term safety of targeting GPR40. Improving the efficacy and the selectivity, thus enlarging the therapeutic window would provide an alternative to develop safe GPR40-targeted therapeutics. Herein, by employing an innovative "three-in-one" pharmacophore drug design strategy, the optimal structural features for GPR40 agonist was integrated into one functional group of sulfoxide, which was incorporated into the ß-position of the propanoic acid core pharmacophore. As a result, the conformational constraint, polarity as well as chirality endowed by the sulfoxide significantly enhanced the efficacy, selectivity and ADMET properties of the novel (S)- 2-(phenylsulfinyl)acetic acid-based GPR40 agonists. The lead compounds (S)-4a and (S)-4s exhibited robust plasma glucose-lowering effects and insulinotropic action during an oral glucose tolerance test in C57/BL6 mice, excellent pharmacokinetic profile and little hepatobiliary transporter inhibition, marginal cell toxicities against human primary hepatocyte at 100 µM.

Evaluation of peripheral blood T-lymphocyte subpopulations features in patients with hepatitis B virus-related acute-on-chronic liver failure based on single-cell sequencing technology / 中华肝脏病杂志

Objective: T lymphocyte exhaustion is an important component of immune dysfunction. Therefore, exploring peripheral blood-exhausted T lymphocyte features in patients with hepatitis B virus-related acute-on-chronic liver failure may provide potential therapeutic target molecules for ACLF immune dysfunction. Methods: Six cases with HBV-ACLF and three healthy controls were selected for T-cell heterogeneity detection using the single-cell RNA sequencing method. In addition, exhausted T lymphocyte subpopulations were screened to analyze their gene expression features, and their developmental trajectories quasi-timing. An independent sample t-test was used to compare the samples between the two groups. Results: Peripheral blood T lymphocytes in HBV-ACLF patients had different differentiation trajectories with different features distinct into eight subpopulations. Among them, the CD4(+)TIGIT(+) subsets (P = 0.007) and CD8(+)LAG3(+) (P = 0.010) subsets with highly exhausted genes were significantly higher than those in healthy controls. Quasi-time analysis showed that CD4(+)TIGIT(+) and CD8(+)LAG3(+) subsets appeared in the late stage of T lymphocyte differentiation, suggesting the transition of T lymphocyte from naïve-effector-exhausted during ACLF pathogenesis. Conclusion: There is heterogeneity in peripheral blood T lymphocyte differentiation in patients with HBV-ACLF, and the number of exhausted T cells featured by CD4(+)TIGIT(+)T cell and CD8(+)LAG3(+) T cell subsets increases significantly, suggesting that T lymphocyte immune exhaustion is involved in the immune dysfunction of HBV-ACLF, thereby identifying potential effective target molecules for improving ACLF patients' immune function.

Convergent synthesis of tetrahydropyranyl side chain of verucopeptin, an antitumor antibiotic active against multidrug-resistant cancers.

A concise synthesis of the tetrahydropyranyl side chain of verucopeptin, an antitumor antibiotic cyclodepsipeptide efficacious against MDR cancers in vivo, is achieved using 12 steps in the longest linear sequence and 21 total steps, in which Julia-Kocienski olefination for the segments coupling, asymmetric hydroxylation as well as stereoselective synthesis of stable tetrahydropyran ring from a D-isoascorbic acid derivative are key steps. This convergent synthetic strategy enables the structural modification and mechanism study of verucopeptin for its clinical applications.

New 4',5'-methylenedioxyflavone derivatives from the whole plant of sarcandra glabra.

Two new natural products named 5,7-dihydroxy-3,3',6,8-tetramethoxy-4',5'-methylenedioxyflavone (1) and 3,3',5,7-tetramethoxy-4',5'-methylenedioxyflavone (2), along with thirteen known compounds, ß-sitosterol (3), desmethoxyyangonin (4), hexadecane (5), 3,9-bis(2,4-di-tert-butylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro [5.5] undecane 3,9-dioxide (6), 2'6'-dihydroxy-4'-methoxydihydrochalcone (7), cardamonin (8), 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone (9), isofraxidin (10), aniba dimer A (11), 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone (12), quercetin (13), quercitrin (14) and isoquercitrin (15) were isolated from Sarcandra glabra (Thunb.) Nakai by various chromatographic methods. Compounds 1, 2, 4, 6, 11, and 12 were isolated from S. glabra for the first time. Their chemical structures were identified through the analysis of NMR and HR-MS spectra. The anti-inflammatory and cytotoxic activities of compounds 1-15 were evaluated in cell assays. The results indicated that compounds 1, 7, 8, 10, 14, and 15 significantly inhibited the NO production in LPS-induced RAW 264.7 murine macrophage cells. Moreover, compounds 1, 3, 4, 7, 8, 9, 10 and 12 exhibited a cytotoxic effect on the human HepG2 cell line.

Metal-free hypervalent iodine-promoted tandem carbonyl migration and unactivated C(Ph)-C(Alkyl) bond cleavage for quinolone scaffold synthesis.

An unexpected iodine(III)-mediated C(sp3)-C(sp2) bond cleavage of 3-(methylamino)-2-(2-substitutedbenzoyl)acrylates for efficient synthesis of privileged scaffold 4-quinolones was described. Notably, a wide range of alkyl groups (e.g. methyl, tert-butyl or alkyl chain) can be conveniently cleaved in this system. The detailed mechanism studies revealed that the transformation proceeded through cascade ipso-cyclization and 1,2-carbonyl migration, the smaller bond energy determined ortho C-C bond cleavage rather than C-H bond cleavage, via an enamine radical intermediate.

Baicalin attenuate diet-induced metabolic syndrome by improving abnormal metabolism and gut microbiota.

In this work, we examined whether baicalin (BC), a bioactive flavonoid in Scutellaria baicalensis Georgi, can reduce high-fat diet (HFD)-induced metabolic syndrome (MetS) in mice. The UPLC-QTOF/MS was used for metabolome profiles analysis, and an analysis of bacterial 16S rDNA in feces was used to examine the effects of BC on gut microbiota composition. Our results showed that BC (400 mg/kg) could reduce the body weight gain, decrease hepatic fat accumulation and abnormal blood lipids, and increase insulin sensitivity after 8 weeks of treatment. BC could reverse the alteration of 7 metabolites induced by HFD and the metabolic pathways responsive to BC intervention including citrate cycle, alanine, aspartate and glutamate metabolism, glycerophospholipid metabolism, and aminoacyl-tRNA biosynthesis. 16S rDNA analysis demonstrated that BC altered the composition and function of gut microbiota in MetS mice. Notably, we found that the change in succinic acid was negatively associated with the changes in Bacteroides and Sutterella, and positively associated with the change in Mucispirillum. Moreover, we confirmed that succinic acid displayed a metabolic protective effect on MetS mice. The antibiotic treatment verified that BC exerts metabolic protection through gut microbiota. Our findings suggested BC may be a potential therapeutic drug to ameliorate diet induced MetS and gut microbiome may be a novel mechanistic target of BC for treatment of MetS.

Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors.

Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the Ptpn11 gene, which regulates cell growth, differentiation and apoptosis via modulating various signaling pathways, such as the RAS/ERK signaling pathway, and participates in the PD-1/PD-L1 pathway governing immune surveillance. It has been recognized as a breakthrough antitumor therapeutic target. Besides, numerous studies have shown that SHP2 plays an important role in the regulation of inflammatory diseases. However, inhibitors targeting the active site of SHP2 lack drug-likeness due to their low selectivity and poor bioavailability, thus none has advanced to clinical development. Recently, allosteric inhibitors that stabilize the inactive conformation of SHP2 have achieved breakthrough progress, providing the clinical proof for the druggability of SHP2 as an antitumor drug target. This paper reviews the recently reported design and discovery of SHP2 small molecule inhibitors, focused on the structure-activity relationship (SAR) analysis of several representative SHP2 inhibitors, outlining the evolution and therapeutic potential of the small molecule inhibitors targeting SHP2.

On-Demand Activation of a Bioorthogonal Prodrug of SN-38 with Fast Reaction Kinetics and High Releasing Efficiency In Vivo.

Although a myriad of bioorthogonal prodrugs have been developed, very few of them present both fast reaction kinetics and complete cleavage. Herein, we report a new bioorthogonal prodrug strategy with both fast reaction kinetics (k2: ∼103 M-1 s-1) and complete cleavage (>90% within minutes) using the bioorthogonal reaction pair of N-oxide and boron reagent. Distinctively, an innovative 1,6-elimination-based self-immolative linker is masked by N-oxide, which can be bioorthogonally demasked by a boron reagent for the release of both amino and hydroxy-containing payload in live cells. Such a strategy was applied to prepare a bioorthogonal prodrug for a camptothecin derivative, SN-38, resulting in 10-fold weakened cytotoxicity against A549 cells, 300-fold enhanced water solubility, and "on-demand" activation upon a click reaction both in vitro and in vivo. This novel bioorthogonal prodrug strategy presents significant advances over the existing ones and may find wide applications in drug delivery in the future.

LuxS modulates motility and secretion of extracellular protease in fish pathogen Vibrio harveyi.

Vibrio harveyi can cause infections and diseases in a variety of marine vertebrates and invertebrates, which are harmful to the aquaculture industry. The LuxS quorum-sensing system regulates the expression of virulence factors in a wide variety of pathogenic bacteria. In this study, an in-frame deletion of the luxS gene was constructed to reveal the role of LuxS in the physiology and virulence of V. harveyi. Statistical analysis showed no significant differences in the growth ability, biofilm formation, antibiotic susceptibility, virulence by intraperitoneal injection, and ability of V. harveyi to colonize the spleen and liver of the pearl gentian grouper between the wild-type (WT) and luxS mutant. However, deletion of luxS decreased the secretion of extracellular protease, while increasing swimming and swarming abilities. Simultaneously, a luxS-deleted mutant showed overproduction of lateral flagella, and an intact luxS complemented this defect. Since motility is flagella dependent, 16 V. harveyi flagella biogenesis related genes were selected for further analysis. Based on quantitative real-time reverse transcription-PCR (qRT-PCR), the expression levels of these genes, including the polar flagella genes flaB, flhA, flhF, flhB, flhF, fliS, and flrA and the lateral flagella genes flgA, flgB, fliE, fliF, lafA, lafK, and motY, were significantly upregulated in the ΔluxS: pMMB207 (ΔluxS+) strain as compared with the V. harveyi 345: pMMB207 (WT+) and C-ΔluxS strains during the early, mid-exponential, and stationary growth phases. Our results indicate that LuxS plays an important role in controlling motility, flagella biogenesis, and extracellular protease secretion in V. harveyi.

Real-world study evaluating the incidence of liver damage conditions in patients with primary liver cancer using immune checkpoint inhibitor-based combination therapy / 中华肝脏病杂志

Objective: To evaluate the incidence of immune checkpoint inhibitor-based combination therapy-induced liver damage in patients with primary liver cancer. Methods: Clinical data of 65 hospitalized cases of primary liver cancer treated with programmed cell death-1 its ligand programmed death-ligand 1 (PD-1/PD-L1) antibody in the Department of Infectious Diseases of the Second Affiliated Hospital of Chongqing Medical University from January 1, 2018 to March 31, 2021 were retrospectively analyzed. The degree of liver injury before and after treatment was assessed according to CTCAE v5.0. Patients were grouped according to gender, age, presence or absence of cirrhosis, baseline Child-Pugh score, BCLC stage, and treatment regimen to compare the incidence of liver injury under different conditions. The χ (2) test or rank-sum test was used for comparison among multiple groups. Results: 46 cases (70.77%) had liver damage of any grade according to the CTCAE V5.0 criteria during the treatment and observation period. All 6 cases who received standardized anti-hepatitis B virus (HBV) treatment developed liver damage. 10 (15.38%), 15 (23.08%), 19 (29.23%), and 2 (3.08%) cases had grade 1, 2, 3, and 4 liver damage respectively. There was no statistically significant difference in the incidence of liver damage between male and female patients (68.33% and 100%, P = 0.180). There was no statistically significant difference in the incidence of liver damage among different age groups (P = 0.245). The incidence of liver damage in cirrhotic and non-cirrhotic group was 72.22%, and 63.64% (P = 0.370), respectively. The incidence of liver damage in patients with baseline Child-Pugh class A, B, and C were 71.43%, 61.11% and 100%, respectively, and the difference was not statistically significant (P = 0.878). The incidence of liver damage was not statistically significantly different under different BCLC stages (P = 1.000). The incidence of liver damage in the PD-1/PD-L1 antibody monotherapy, PD-1/PD-L1 antibody combined with targeted drug therapy, and PD-1/PD-L1 antibody combined with TACE/radiofrequency ablation treatment group were 60.00%, 67.85%, and 86.67%, respectively. There was no statistically significant difference in the incidence of liver damage between the treatment regimen (P = 0.480). Conclusion: Immune checkpoint inhibitor therapy-induced liver damage is common in patients with primary liver cancer; however, it rarely severely endangers the patient's life. Additionally, patient's gender, age, presence or absence of cirrhosis, baseline liver function, BCLC stage and the immunotherapy regimen has no effect on the incidence of immune-related liver damage.

Current progress and quality of radiomic studies for predicting EGFR mutation in patients with non-small cell lung cancer using PET/CT images: a systematic review.

OBJECTIVES: To assess the methodological quality of radiomic studies based on positron emission tomography/computed tomography (PET/CT) images predicting epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). METHODS: We systematically searched for eligible studies in the PubMed and Web of Science datasets using the terms "radiomics", "PET/CT", "NSCLC", and "EGFR". The included studies were screened by two reviewers independently. The quality of the radiomic workflow of studies was assessed using the Radiomics Quality Score (RQS). Interclass correlation coefficient (ICC) was used to determine inter rater agreement for the RQS. An overview of the methodologies used in steps of the radiomics workflow and current results are presented. RESULTS: Six studies were included with sample sizes of 973 ranging from 115 to 248 patients. Methodologies in the radiomic workflow varied greatly. The first-order statistics were the most reproducible features. The RQS scores varied from 13.9 to 47.2%. All studies were scored below 50% due to defects on multiple segmentations, phantom study on all scanners, imaging at multiple time points, cut-off analyses, calibration statistics, prospective study, potential clinical utility, and cost-effectiveness analysis. The ICC results for majority of RQS items were excellent. The ICC for summed RQS was 0.986 [95% confidence interval (CI): 0.898-0.998]. CONCLUSIONS: The PET/CT-based radiomics signature could serve as a diagnostic indicator of EGFR mutation status in NSCLC patients. However, the current conclusions should be interpreted with care due to the suboptimal quality of the studies. Consensus for standardization of PET/CT-based radiomic workflow for EGFR mutation status in NSCLC patients is warranted to further improve research. ADVANCES IN KNOWLEDGE: Radiomics can offer clinicians better insight into the prediction of EGFR mutation status in NSCLC patients, whereas the quality of relative studies should be improved before application to the clinical setting.

Electronically reconfigurable unit cell for transmit-reflect-arrays in the X-band.

This paper proposes an electronically reconfigurable unit cell for transmit-reflect-arrays in the X-band, which makes it possible to control the reflection or transmission phase independently by combining the mechanisms of reconfigurable transmitarrays and reconfigurable reflectarrays. The fabricated unit cell was characterized in a waveguide simulator. The return loss in the reflection mode and insertion loss in the transmission mode are smaller than 1.8 dB for all states at 10.63 GHz, and a 1-bit phase shift for both modes is achieved within 180° ± 10°. When compared to full-wave electromagnetic simulation results, the proposed unit cell shows good results and is thus verified.

Endovascular Intervention with a Low-profile Visualized Intraluminal Support Stent Versus Surgical Clipping for Blood Blister-like Aneurysms : A Retrospective Study.

PURPOSE: Blood blister-like aneurysms (BBAs) have a high risk of early recurrence and postoperative rebleeding. This study compared the clinical outcomes and complications between endovascular intervention with low-profile visualized intraluminal support (LVIS) stent-assisted coiling and the surgical clipping in patients with BBAs. METHODS: This retrospective study enrolled 39 patients with BBAs who underwent endovascular intervention with LVIS stent-assisted coiling (n = 21) or surgical clipping (n = 18) between January 2013 and July 2018. Primary outcomes were mortality and modified Rankin scale (mRS). Secondary outcomes were hospital stay, intensive care unit (ICU) stay and operation parameters. Complications were also retrospectively collated. RESULTS: At baseline, the two groups were well balanced in patient characteristics. The hospital stays, ICU stays, operation time and intraoperative infusion volume were all significantly lower in LVIS group than that in clipping group (p < 0.05). A second operation was performed in 6 cases in the clipping group but none in the LVIS group (p = 0.006). The mean mRS score in the LVIS group was significantly lower than that of the clipping group both at hospital discharge and final follow-up (p < 0.001). Adverse outcomes occurred in 1 case in LVIS group and 7 in clipping group, with significant difference (p = 0.015). Complications were reported in 8 cases in LVIS group and 16 cases in clipping group, with significant difference (p < 0.001). CONCLUSION: The endovascular intervention with LVIS stent-assisted coiling has better prognosis than surgical clipping. It decreased the risk of a second operation and procedure-related complications compared with surgical clipping.

[Seasonal Characteristics and Source Analysis of Water-soluble Inorganic Ions in PM2.5 in Suqian City].

To study the seasonal pollution characteristics and sources of water-soluble inorganic ions in atmospheric PM2.5 in Suqian City, 171 samples were collected at three monitoring points, which were in the water vapor channel, from May 2017 to January 2018. The mass concentrations of PM2.5 and nine water-soluble inorganic ions were analyzed. The results showed that the annual average concentration of water-soluble inorganic ions in PM2.5 in Suqian City was (44.08±34.61) µg ·m-3, accounting for 41.8% of PM2.5. The concentrations of these species were in the order of ρ(NO3-) > ρ(SO42-) > ρ(NH4+) > ρ(ρl-) > ρ(Na+) > ρ(Ca2+) > ρ(K+) > ρ(F-) > ρ(Mg2+); NO3-, SO42-, and NH4+ accounted for 75.6% of the total water-soluble ions. The annual average ratio of ρ(NO3-) to ρ(SO42-) was 1.53±0.88, indicating that mobile sources contributed more to PM2.5 pollution. Based on the correlation analysis of NH4+ and SO42-, NO3- may exist in the form of (NH4)2 SO4, NH4HSO4, or NH4NO3. According to the principal component analysis, secondary transformation, industrial pollution, biomass burning, and dust were the major sources of water-soluble inorganic ions. PM2.5concentrations were positively related to relative humidity in winter. Water vapor transmission is more likely to promote PM2.5 accumulation in winter.

Acute fluorene-9-bisphenol exposure damages early development and induces cardiotoxicity in zebrafish (Danio rerio).

Fluorene-9-bisphenol (BHPF) is a substitute for bisphenol A (BPA), which is widely used to manufacture plastic products. Previous studies indicate that BHPF has an anti-estrogenic effect and induces cytotoxicity in mice oocytes. However, the effects of acute BHPF exposure on the aquatic organism obtain little attention. In this study, a series of BHPF concentrations (1 µM, 2 µM, 5 µM, 10 µM, 20 µM) was used to exposed zebrafish embryos from 2 h post-fertilization (hpf). The results showed the LC50 at 96hpf was 2.88 µM (1.01 mg/L). Acute exposure induced malformation in morphology, and retarded epiboly rate at 10hpf, increased apoptosis. Moreover, acute BHPF exposure led cardiotoxicity, by impeding cardiac looping, decreasing cardiac contractility (reducing the stroke volume and cardiac output, decreasing fractional shortening of ventricle). Besides that, BHPF exposure altered the expression of cardiac transcriptional regulators and development related genes. In conclusion, acute BHPF exposure induced developmental abnormality, retarded cardiac morphogenesis and injured the cardiac contractility. This study indicated BHPF would be an unneglected threat for the safety of aquatic organisms.

Effect of glucose metabolism on hypothalamus-pituitary-thyroid axis / 医学研究生学报

Glucose is the basic metabolic substrate and main source of energy for the body. A complex neuroendocrine system regulate blood glucose concertration to keep it at a constant level. Thyroid hormones participate in the regulation of glucose metabolism through the PI3K/ERK and other signaling pathways. At the same time, abnormal glucose metabolism can cause the abnormal regulation of hypothalamus pituitary thyroid axis. In this paper, we review the change and molecular mechanism of thyroid hormone, thyroid stimulating hormone and thyroid releasing hormone in Hypoglycemia and Hyperglycemia.

Generation of wideband vortex beam with different OAM modes using third-order meta-frequency selective surface.

Orbital angular momentum (OAM) beam generators have attracted tremendous interests recently due to their excellent performance and potential applications in wireless communication. However, the existing transmissive OAM generators suffer from several limitations, such as narrow bandwidth, high profile and low efficiency. In this study, a new wideband third-order meta-frequency selective surface (meta-FSS) for generating focusing vortex beam is developed. The proposed meta-FSS element is designed at X- band with a third-order band-pass filter property, which exhibits the merits of low profile, high transmissivity, and large angular stability. By employing the proposed meta-FSS element, prototypes of OAM generators for + 1 and -2 modes are designed, fabricated, and measured. Experimental results verify the ability of the proposed design to convert an incident left/right-handed circularly polarized (L/RHCP) spherical wave into a transmitted R/LHCP vortex carrying OAM wave from 9.0 GHz to 11.0 GHz with high mode purity. A good agreement is achieved between the experimental and numerical results, which demonstrates that the proposed structure paves the wave for generating desired OAM modes, and provides new possibility for designing novel low-profile wireless communication devices.

Venlafaxine plus melatonin ameliorate reserpine-induced depression-like behavior in zebrafish.

Venlafaxine (VEN) is one of the first clinical drugs for the treatment of depression. Long-term use may cause a potentially life-threatening serotonin syndrome. Melatonin (MT) could ameliorate depression behavior. Therefore, the aim of this study was to investigate the antidepressant effects of venlafaxine in combination with melatonin on zebrafish. Reserpine was used to induce depression-like behavioral zebrafish. To explore the effects of combined use of venlafaxine and melatonin on depression-like zebrafish induced by reserpine. We tested the depressive behavior of adult zebrafish through a novel tank test, and evaluated the levels of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) in zebrafish brain using enzyme-linked immunosorbent assay (ELISA), besides that the gene expression of serotonin transporters a (serta), dopamine transporters (dat) and norepinephrine transporters (net), vesicular monoamine transporter2 (vmat2) and monoamine oxidase (mao) were evaluated by qRT-PCR. The results showed that, compared with reserpine-only group, venlafaxine (VEN, 0.025 mg/L) and melatonin (MT, 1 µM) increased the parameters of exploration in the top of the tank and decreased freezing behavior significantly. Compared with reserpine-only group, the use of VEN combined with MT increased serotonin and norepinephrine levels significantly, while there was no obvious difference in dopamine content. The results of qRT-PCR showed that the use of VEN combined with MT significantly reduced the expression of serta and promoted the expression of vmat2, but had no significant effect on the expression of net, dat and mao. The results indicated that venlafaxine combined with melatonin showed more effective role to remedy the depressive symptoms in zebrafish, providing a reference for the clinical application of antidepressants.