Mechanism of GW117 antidepressant action: melatonin receptor-mediated regulation of sleep rhythm.

Alterations in circadian sleep patterns constitute a salient manifestation in major depressive disorder. GW117, an emergent antidepressant, functions as an agonist for melatonin 1 and melatonin 2 (MT1/MT2) receptors, in tandem with antagonism of the serotonin (5-HT) 2C receptor. The present investigation is dedicated to elucidating the role and underlying mechanisms by which GW117 ameliorates circadian sleep disruptions. Utilizing an adapted chronic unpredictable mild stress protocol, we induced a depressive-like phenotype and perturbed circadian rhythms in rodent models. Our methodological approach integrated quantitative polymerase chain reaction (qPCR) in real-time, enzyme-linked immunosorbent assay (ELISA), and immunoblotting techniques to probe alterations in the expression of core circadian genes and homeostatic sleep markers. The impact of GW117 was assessed across various dosages (10, 20, and 40 mg/kg) on these molecular signatures. In a parallel examination, we evaluated the influence of GW117 (administered at 15, 40, and 60 mg/kg) on the sleep patterns of healthy mice. The results showed that GW117 significantly improved sleep-wake circadian rhythms, altered sleep architecture, and shortened sleep latency. Furthermore, GW117 increased the expression of several clock genes in the hypothalamus of chronic unpredictable mild stress model rats and normal mice. It also regulated circadian biomarkers, including melatonin and cortisol. Based on our findings, we propose that the beneficial effects of GW117 on sleep rhythms may be due to the melatonin system-mediated activation of the Wnt/ß-catenin signaling pathway.

[Characteristics and Sources of PM2.5 Pollution During Winter in Handan City from 2016 to 2020].

To explore the characteristics and sources of PM2.5 pollution in winter of Handan City in the past five years, PM2.5 samples were collected in winter of 2016 to 2020, and eight types of water-soluble inorganic ions were analyzed. The principal component analysis(PCA) model was used to analyze the types of pollution sources, and the backward trajectory and potential source contribution factor(PSCF) were used to simulate the transport trajectory and pollution sources. The results showed that the PM2.5 concentration in winter of 2018 was the highest, increasing by 60.44%, 25.46%, 91.43%, and 21.53% compared with that in 2016, 2017, 2019, and 2020, respectively. In the winter of 2020, the concentration of water-soluble inorganic ions(WSIIs) decreased by 18.86% compared with that in 2016, and WSIIs/PM2.5 decreased to 26.69%. The PM2.5 concentration(110.20-209.65 µg·m-3) at night was higher than that in the daytime(95.21-193.00 µg·m-3). The concentration of NO3- and NH4+ increased more at night. On the contrary, the concentration and proportion of Cl-decreased annually. In the winter of 2020, the daytime concentrations of K+, Ca2+, Na+, and Mg2+ decreased by 69.72%, 97.10%, 90.91%, and 74.51% compared with that of 2018, and the night concentrations decreased by 66.67%, 95.38%, 91.67%, and 77.78%, respectively. In 2020, the concentrations of NO3-, SO42-, and NH4+ on polluted days were 4.90, 5.80, and 5.20 times those on non-polluted days, with the largest increase in five years. PCA results showed that the main sources of pollution were secondary sources, coal sources, biomass combustion sources, and road and building dust. The backward trajectory and PSCF analysis results showed that pollution transport continued to exist between south-central Mongolia and central Inner Mongolia in winter and was influenced by the transport between northern Henan and Handan and central Hebei and Handan in winter of 2016 and 2017, whereas the latter had a greater impact in winter of 2018-2020.

[Chemical Characteristics and Sources of Atmospheric Aerosols in the Surrounding District of a Heavily Polluted City in the Southern Part of North China].

In order to explore the chemical composition and source profiles of atmospheric particulate matter in winter in the northern area of Handan, a heavily polluted city in the southern part of North China, PM1 and PM2.5 samples were collected and analyzed from November 23 to December 12, 2020. During the observation period, the daily average ρ(PM1)and ρ(PM2.5) were 114.53 µg·m-3 and 124.25 µg·m-3, respectively, and the ratio of PM1/PM2.5 was 83.3%-95.3%, which was significantly higher than those of other cities in the Beijing-Tianjin-Hebei region, indicating that air pollution of fine particulate matter, especially sub-micron particulate matter, was more serious in Handan. Compared with that during clean days, SNA (SO42-, NO3-, and NH4+) in PM1 increased by 14.5% during heavy pollution, and SNA in PM2.5 increased by 15.2%; the nitrogen oxidation rate (NOR) in particular increased by three times on heavy pollution days. With the deepening of pollution, the proportion of secondary organic carbon (SOC) in PM1 and PM2.5 increased by 22.0% and 12.5%, respectively. SOC tended to accumulate in small particles, whereas the proportion of primary organic carbon (POC) and elemental carbon (EC) in PM1 decreased by 15.4% and 6.6%, and the POC and EC in PM2.5 decreased by 8.2% and 4.3%, respectively. The above results indicated that secondary formation played an important role in the heavy pollution of particulate matter. With the aggravation of air pollution, the liquid water content of the particles increased, and both the sulfur oxidation ratio (SOR) and nitrogen oxidation ratio (NOR) increased, indicating that the aqueous phase chemical reaction made an important contribution to the formation of secondary inorganics. With the deepening of pollution, inorganic elements were on the rise; Se, As, Pb, and Zn were highly enriched in inorganic elements. The results of principal component analysis (PCA) showed that secondary formation, industrial emissions, vehicle exhaust, and biomass burning emissions were the main sources of particulate pollutants. The results of potential source contribution factor analysis (PSCF) showed that the high value areas of SO42-, NO3-, EC, OC, and inorganic elements were mainly from the north and southwest directions of the observation area.

[Effect of injecting mouse nerve growth factor in different ways on motor development, cerebral hemodynamics and biochemical metabolism in children with cerebral palsy].

OBJECTIVE: To compare the effect of acupoint injection and intramuscular injection with mouse nerve growth factor (mNGF) on gross motor function development of children with cerebral palsy (CP), and explore the treatment mechanism. METHODS: A total of 63 children with CP were randomly divided into an observation group (32 cases, 4 cases dropped off ) and a control group (31 cases, 3 cases dropped off). Based on the routine rehabilitation therapy, the control group received intramuscular injection of mNGF(18 µg/2 mL), and the observation group received acupoint injection of mNGF at Xinshu (BL 15), Ganshu (BL 18), Pishu (BL 20), Shenshu (BL 23), Sanjiaoshu (BL 22), Shenting (GV 24), Baihui (GV 20), Fengfu (GV 16), Dazhui (GV 14), etc. Of them, 5-6 acupoints alternately were selected each time, and each acupoint was given 0.3-0.5 mL, totally 18 µg/2 mL. Both treatment were carried out once every other day for six months. Before and after treatment, the children's development of brain function was assessed using gross motor function classification system (GMFCS). Before treatment (T0), after 2 (T2), 4 (T4) and 6 (T6) months of treatment, the motor function was evaluated by gross motor function measure (GMFM-88). The systolic peak velocity (Vs), mean velocity (Vm) and vascular resistance index (RI) of anterior cerebral artery (ACA) and middle cerebral artery (MCA) were measured, and the level of N-acetyl aspartate acid (NAA), choline (Cho), lactate (Lac) and creatine (Cr) from the basal ganglia, thalamus and periventricular white mater were detected by magnetic resonance spectroscopy (MRS) technology with MAGNETOM Skyra3.0T magnetic resonance imaging system before and after treatment. RESULTS: Compared with before treatment, the GMFCS classification of the observation group after treatment was significantly improved (P<0.05); after treatment, the difference of GMFCS classification between the two groups was not significant (P>0.05), however, the observation group had a 3.142 times of feasibility for good gross motor function development by more than level 1 compared to the control group (P<0.05). After 2, 4, and 6 months of treatment, the GMFM-88 scores of the two groups showed an upward trend (P<0.01), and the increase of the observation group was greater than that of the control group (P<0.05). Compared with before treatment, in the ACA and MCA, the Vs and Vm increased, RI decreased in both groups after treatment (P<0.01), and in the brain, NAA/Cr increased, Cho/Cr and Lac/Cr decreased (P<0.01), and after treatment, the Vs, Vm of ACA and MCA and NAA/Cr of brain in the observation group were higher than those in the control group (P<0.05), and the RI of ACA and MCA and Cho/Cr and Lac/Cr of brain in the observation group were lower than those in the control group (P<0.05). CONCLUSION: The mNGF acupoint injection has a better effect on the gross motor function in the children with cerebral palsy compared with the intramuscular injection, and the mechanism may be associated with exhibiting the double effects of acupoint effect and the targeting therapy of drug, which can effectively improve the cerebral hemodynamics and the metabolism of cerebral nervous substances.

Mouse strain differences in SSRI sensitivity correlate with serotonin transporter binding and function.

Selective serotonin reuptake inhibitors (SSRIs) bind 5-HT transporters, leading to the accumulation of 5-HT and amelioration of depression. Although different mouse strains show varying sensitivity to SSRIs in mouse models of depression, the underlying mechanism of these strain differences remains unclear. Here, the SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2J mice but not C57BL/6J mice, whereas fluoxetine showed the opposite results. Paroxetine similarly reduced immobility time in both strains. The affinity of citalopram for the 5-HT transporter was 700-fold higher in DBA/2J mice than in C57BL/6J mice, whereas the affinity of fluoxetine was 100-fold higher in C57BL/6J mice than in DBA/2J mice. Furthermore, high citalopram concentrations were required for [3H]5-HT uptake in C57BL/6J but not in DBA/2J mouse cortical synaptosomes, whereas fluoxetine showed the opposite results. The effects of paroxetine on 5-HT transporter binding and synaptosomal 5-HT uptake were similar in the two strains. These results suggest that immobility duration depends on 5-HT transporter binding levels, which lead to apparent strain differences in immobility time in the FST and TST. Furthermore, differences in 5-HT transporter binding may cause variations in SSRI effects on behaviors.

Effect of Tongxinluo on pulmonary hypertension and pulmonary vascular remodeling in rats exposed to a low pressure hypoxic environment.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL), which is a Chinese medicine rooted from traditional used herbs, has been used in clinic to treat cardiovascular and cerebrovascular diseases. However, it remains unknown whether TXL alleviates low pressure hypoxic pulmonary hypertension. AIM OF THE STUDY: Here, we aimed to observe the influence of TXL on pulmonary hypertension in a rat model that exposed to high altitude environment characterized by low pressure hypoxia. MATERIALS AND METHODS: A total of 32 male Sprague-Dawley rats were divided into four groups: control group (normal pressure and normoxia), pulmonary hypertension group (PAH, the parameter is equal to that in altitude 5000m), TXL group (rats living in environment equal to that at altitude of 5000m received TXL treatment), vardenafil group (VDNF, rats living in environment equal to that altitude of 5000m received vardenafil treatment). The high altitude environment was created in chamber by adjusting the inner pressure and oxygen content concomitantly. Before entering the chamber, the TXL group was given TXL (1.2gkg-1d-1) for 28 days, and the VDNF group was given VDNF (0.1gkg-1d-1) for 28 days. After 28 days, the mean pulmonary artery pressure (mPAP) and right ventricular pressure was measured using right heart catheterization. The weight of the right ventricle (RV), left ventricle (LV) and interventricular septum (IVS) was measured, and the right ventricular mass index was calculated. Lung tissue was subjected to hematoxylin and elastic fiber staining, and the medial wall thickness (MT), medial wall cross-sectional area (MA), MT%, and MA% were measured. Proliferative activity within the pulmonary arteries was quantified by Ki67staining. RESULTS: After 28 days, as compared with that in normal control group, animals living in the chamber (PAH group) showed a significant increase in mPAP( 47.5mmHg versus 18mmHg), RV/LV+IVS (0.45 versus 0.21) and MA% (78% versus 44%), respectively. Administration of TXL resulted in a significant decrease of 20mmHg in mPAP, returning of RV/LV+IVS to 0.27, and a 40% reduction in MT% compared with that in PAH group. In the VDNF group, RV/LV+IVS and MT% was 0.268 and 38.77, significantly lower than that in PAH group. While, mPAP increased by 12.5mmHg with treatment by VDNF. In contrast to the PAH group, alpha- Smooth Muscle Actin (α-SMA reduced by 19% in the TXL group (p=0.005) and 16% in the VDNF group (p=0.01). Ki67 expression in the VDNF group was significantly lower than the PAH group (P<0.01). Ki67 expression in the TXL group was significantly lower than the PAH group (P<0.01). Compared with the VDNF group, the indexes above reduced in the TXL group. Our results indicate that TXL significantly reduces pulmonary artery pressure, right ventricular hypertrophy, pulmonary small artery wall thickness, and luminal stenosis. In addition, smooth muscle proliferation markedly decreased and muscular artery decreased. However, TXL was unable to restore parameters to control levels. CONCLUSIONS: The automatic-adjusted low pressure hypoxic chamber was capable of establishing a pulmonary hypertension rat model at an altitude of 5000m. Compared with VDNF, TXL decreased mPAP and right ventricular hypertrophy index (RVHI) in the pulmonary hypertension rat model, and prevented vascular remodeling by reducing small pulmonary artery thickening, smooth muscle thickening and proliferation. Thus, TXL may be a potential treatment for pulmonary hypertension.

Homology modeling and virtual screening for inhibitors of lipid kinase PI(4)K from Plasmodium.

Malaria parasite strains have emerged to tolerate the therapeutic effects of the prophylactics and drugs presently available. Recent studies have shown that KAI715 and its analogs inhibit malaria parasites growth by binding to lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) of the parasites. Therefore, targeting PI(4)K may open up new avenues of target-based drug discovery to identify novel anti-malaria drugs. In this investigation, we describe the discovery of novel potent PfPI(4)K (PI(4)K from P. falciparum) inhibitors by employing a proposed hybrid virtual screening (VS) method, including pharmacophore model, drug-likeness prediction and molecular docking approach. 3D structure of PfPI(4)K has been established by homology modeling. Pharmacophore model HypoA of PfPI(4)K inhibitors has been developed based on the ligand complexed with its corresponding receptor. 174 compounds with good ADMET properties were carefully selected by a hybrid virtual screening method. Finally, the 174 hits were further validated by using a new pharmacophore model HypoB built based on the docking pose of BQR685, and 95 compounds passed the last filter. These compounds would be further evaluated by biological activity assays. The molecular interactions of the top two potential inhibitors with the active site residues are discussed in detail. These identified hits can be further used for designing the more potent inhibitors against PfPI(4)K by scaffold hopping, and deserve consideration for further structure-activity relationship (SAR) studies.