Objective To investigate the value of quantitative parameters of diffusion weighted imaging(DWI)based on mono-expo-nential model(MEM),diffusion kurtosis imaging(DKI)model,and stretched-exponential model(SEM)in predicting the efficacy of neoadjuvant therapy in locally advanced gastric cancer(LAGC).Methods Forty LAGC patients who underwent MRI examinations before neoadjuvant therapy and before radical surgery were prospectively enrolled.A radiologist delineated lesions on DWI images and acquired quantitative parameters before and after treatment,including lesion volume,apparent diffusion coefficient(ADC)of MEM,mean diffusivity(MD)and mean kurtosis(MK)of DKI model,distribution diffusion coefficient(DDC),and α of SEM.According to pathological tumor regression grade(TRG),the patients were stratified into good response group(TRG 0-1)and poor response group(TRG 2-3).The pre-treatment parameters and Δ of pre-and post-treatment parameters were compared between the two groups with Mann-Whitney U test;multivariate analysis was performed with binary logistic regression.Multiple DWI models and the combined model were established,and the prediction efficiency of each model was calculated.Results There was no significant differ-ence in each parameter before neoadjuvant therapy between the two groups(P>0.05).The delta of volume,ΔADC,ΔMD,and ΔDDC pre-and post-treatment were all statistically different between the two groups(P<0.05).The area under the curve(AUC)of ΔADC,ΔMD,and ΔDDC in predicting good response for LAGC were 0.900,0.806,and 0.762,respectively.The AUC of the combined model was 0.946.Conclusion Quantitative parameters of MEM,DKI model,and SEM can help predict the efficacy of neoadju-vant-treated LAGC patients.

Objective Network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which the active components of Piper nigrum(PN)regulate depressive-like behaviors in chronic restraint stress(CRS)mice.Methods The major chemical components and targets of PN were screened using the Traditional Chinese Medicine Systems Pharmacology database.Targets related to ferroptosis and depression were obtained from the Online Mendelian Inheritance in Man,GeneCards,and FerrDB databases.The intersecting targets were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Gnomes(KEGG)pathway enrichment analyses,and molecular docking was performed to validate the binding capacities between the core targets and their corresponding active components.Finally,we established a CRS mouse model.Mice were treated with PN 75,150,and 300 mg/kg for 4 weeks,followed by behavioral assessments and reverse transcription-quantitative polymerase chain reaction(RT-qPCR)to verify the expression of core genes.Results Nine active components were screened from PN,corresponding to 27 targets,and 8377 targets related to depression and 547 targets associated with ferroptosis were screened from the databases.The intersection of these three sets resulted in 25 target genes.KEGG enrichment analysis revealed that these core targets were predominantly enriched in signaling pathways,including cholinergic synapses,serotonergic synapses,and neuroactive ligand-receptor interactions.Molecular docking result showed that the main active components of PN had strong binding affinities for the targets CHRM2,SLC6A4,PTGS2,and SLC6A2.Behavioral assessments demonstrated that PN significantly increased the sucrose preference index(P＜0.01,P＜0.001),reduced immobility time in the tail suspension and forced swimming tests(P＜0.01,P＜0.001),and enhanced exploratory behavior in the open field test(P＜0.05.P＜0.01,P＜0.001).PN significantly reduced the serum levels of inflammation markers(P＜0.05.P＜0.01,P＜0.001),as shown by enzyme-linked immunosorbent assay,and neurotransmitter analysis revealed that PN significantly increased the levels of serotonin and acetylcholine in the mouse hippocampus(P＜0.05).RT-qPCR showed that PN demonstrated the mRNA expression of SLC6A4(P＜0.05.P＜0.01,P＜0.001).Conclusions PN may improve depressive-like behavior in mice by modulating serotonin and acetylcholine levels,inhibiting inflammatory responses,participating in immune regulation,and exerting neuroprotective effects.

Objective To investigate the value of quantitative parameters of diffusion weighted imaging(DWI)based on mono-expo-nential model(MEM),diffusion kurtosis imaging(DKI)model,and stretched-exponential model(SEM)in predicting the efficacy of neoadjuvant therapy in locally advanced gastric cancer(LAGC).Methods Forty LAGC patients who underwent MRI examinations before neoadjuvant therapy and before radical surgery were prospectively enrolled.A radiologist delineated lesions on DWI images and acquired quantitative parameters before and after treatment,including lesion volume,apparent diffusion coefficient(ADC)of MEM,mean diffusivity(MD)and mean kurtosis(MK)of DKI model,distribution diffusion coefficient(DDC),and α of SEM.According to pathological tumor regression grade(TRG),the patients were stratified into good response group(TRG 0-1)and poor response group(TRG 2-3).The pre-treatment parameters and Δ of pre-and post-treatment parameters were compared between the two groups with Mann-Whitney U test;multivariate analysis was performed with binary logistic regression.Multiple DWI models and the combined model were established,and the prediction efficiency of each model was calculated.Results There was no significant differ-ence in each parameter before neoadjuvant therapy between the two groups(P>0.05).The delta of volume,ΔADC,ΔMD,and ΔDDC pre-and post-treatment were all statistically different between the two groups(P<0.05).The area under the curve(AUC)of ΔADC,ΔMD,and ΔDDC in predicting good response for LAGC were 0.900,0.806,and 0.762,respectively.The AUC of the combined model was 0.946.Conclusion Quantitative parameters of MEM,DKI model,and SEM can help predict the efficacy of neoadju-vant-treated LAGC patients.

Objective Network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which the active components of Piper nigrum(PN)regulate depressive-like behaviors in chronic restraint stress(CRS)mice.Methods The major chemical components and targets of PN were screened using the Traditional Chinese Medicine Systems Pharmacology database.Targets related to ferroptosis and depression were obtained from the Online Mendelian Inheritance in Man,GeneCards,and FerrDB databases.The intersecting targets were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Gnomes(KEGG)pathway enrichment analyses,and molecular docking was performed to validate the binding capacities between the core targets and their corresponding active components.Finally,we established a CRS mouse model.Mice were treated with PN 75,150,and 300 mg/kg for 4 weeks,followed by behavioral assessments and reverse transcription-quantitative polymerase chain reaction(RT-qPCR)to verify the expression of core genes.Results Nine active components were screened from PN,corresponding to 27 targets,and 8377 targets related to depression and 547 targets associated with ferroptosis were screened from the databases.The intersection of these three sets resulted in 25 target genes.KEGG enrichment analysis revealed that these core targets were predominantly enriched in signaling pathways,including cholinergic synapses,serotonergic synapses,and neuroactive ligand-receptor interactions.Molecular docking result showed that the main active components of PN had strong binding affinities for the targets CHRM2,SLC6A4,PTGS2,and SLC6A2.Behavioral assessments demonstrated that PN significantly increased the sucrose preference index(P＜0.01,P＜0.001),reduced immobility time in the tail suspension and forced swimming tests(P＜0.01,P＜0.001),and enhanced exploratory behavior in the open field test(P＜0.05.P＜0.01,P＜0.001).PN significantly reduced the serum levels of inflammation markers(P＜0.05.P＜0.01,P＜0.001),as shown by enzyme-linked immunosorbent assay,and neurotransmitter analysis revealed that PN significantly increased the levels of serotonin and acetylcholine in the mouse hippocampus(P＜0.05).RT-qPCR showed that PN demonstrated the mRNA expression of SLC6A4(P＜0.05.P＜0.01,P＜0.001).Conclusions PN may improve depressive-like behavior in mice by modulating serotonin and acetylcholine levels,inhibiting inflammatory responses,participating in immune regulation,and exerting neuroprotective effects.

Objective:To investigate the effect of tripartite motif-containing protein 59 (TRIM59) on glucose metabolism in macrophages and its role in regulating hypoxia-inducible factor-1α (HIF-1α)/IL-10 axis in macrophages under inflammatory conditions.Methods:The differentially expressed genes between macrophages with high expression of TRIM59 and control cells transfected with empty TRIM59 plasmid were analyzed by GO and KEGG. The expression of HIF-1α by RAW264.7 macrophages with high expression of TRIM59 was detected at different time points after lipopolysaccharide (LPS) stimulation by RT-qPCR and Western blot. Bone marrow was isolated from TRIM59-cKO and TRIM59 flox/flox mice and induced to differentiate into bone marrow-derived macrophages (BMDMs). These BMDMs were stimulated with LPS and the supernatants of cell culture were collected at 3, 6, 12 and 24 h after stimulation to detect IL-10 level by ELISA. In addition, mouse models of cecal ligation and puncture (CLP) were established, and bronchoalveolar lavage fluid (BALF) samples were collected at the same time points to detect IL-10 level by ELISA. Histopathological changes in lung tissues were observed after HE staining. Results:There was a significant change in glucose metabolism-related genes in macrophages with high expression of TRIM59, and the content of lactic acid increased significantly. Compared with the control group, the expression of HIF-1α at mRNA level in BMDMs from TRIM59-cKO mice decreased after LPS stimulation ( P<0.05); the level of IL-10 increased at 3 h and 24 h in the TRIM59-cKO group, but there was no significant difference in IL-10 level at 6 h or 12 h between the two groups. In the TRIM59-cKO mouse model of CLP, the levels of IL-10 in the BALF samples increased with time, but decreased at 24 h. The level of IL-10 was higher in the TRIM59-cKO mouse model group than that in the control group at each time point ( P<0.05 or P<0.01). Conclusions:TRIM59 can inhibit inflammation and lung injury by decreasing HIF-1α-mediated lactate secretion and IL-10 expression in macrophages. This study provides a new idea for developing novel anti-sepsis drugs based on TRIM59.

Neuropathic pain(NP) has similar phenotypes but different sequential neuroinflammatory mechanisms in the pathological process. It is of great significance to inhibit the initiation of neuroinflammation, which has become a new direction of NP treatment and drug development in recent years. Mongolian drug Naru-3 is clinically effective in the treatment of trigeminal neuralgia, sciatica, and other NPs in a short time, but its pharmacodynamic characteristics and mechanism of analgesia are still unclear. In this study, a spinal nerve ligation(SNL) model simulating clinical peripheral nerve injury was established and the efficacy and mechanism of Naru-3 in the treatment of NPs was discussed by means of behavioral detection, side effect evaluation, network analysis, and experimental verification. Pharmacodynamic results showed that Naru-3 increased the basic pain sensitivity threshold(mechanical hyperalgesia and thermal radiation hyperalgesia) in the initiation of SNL in animals and relieved spontaneous pain, however, there was no significant effect on the basic pain sensitivity threshold and motor coordination function of normal animals under physiological and pathological conditions. Meanwhile, the results of primary screening of target tissues showed that Naru-3 inhibited the second phase of injury-induced nociceptive response of formalin test in mice and reduced the expression of inflammatory factors in the spinal cord. Network analysis discovered that Naru-3 had synergy in the treatment of NP, and its mechanism was associated with core targets such as matrix metalloproteinase-9(MMP9) and interleukin-1β(IL-1β). The experiment further took the dorsal root ganglion(DRG) and the stage of patho-logical spinal cord as the research objects, focusing on the core targets of inducing microglial neuroinflammation. By means of Western blot, immunofluorescence, agonists, antagonists, behavior, etc., the mechanism of Naru-3 in exerting NP analgesia may be related to the negative regulation of the MMP9/IL-1β signaling pathway-mediated microglia p38/IL-1β inflammatory loop in the activation phase. The relevant research enriches the biological connotation of Naru-3 in the treatment of NP and provides references for clinical rational drug use.
Rats ; Mice ; Animals ; Matrix Metalloproteinase 9/metabolism* ; Rats, Sprague-Dawley ; Neuroinflammatory Diseases ; Interleukin-1beta/metabolism* ; Spinal Cord/metabolism* ; Signal Transduction ; Hyperalgesia/metabolism* ; Neuralgia/metabolism*

The Baimai Ointment with the effect of relaxing sinew and activating collaterals demonstrates a definite effect on Baimai disease with pain, spasm, stiffness and other symptoms, while the pharmacodynamic characteristics and mechanism of this agent remain unclear. In this study, a rat model of chronic compression of L4 dorsal root ganglion(CCD) was established by lumbar disc herniation, and the efficacy and mechanism of Baimai Ointment in the treatment of CCD were preliminarily explored by behavioral tests, side effect evaluation, network analysis, antagonist and molecular biology verification. The pharmacodynamic experiment indicated that Baimai Ointment significantly improved the pain thresholds(mechanical pain, thermal pain, and cold pain) and gait behavior of CCD model rats without causing tolerance or obvious toxic and side effects. Baimai Ointment inhibited the second-phase nociceptive response of mice in the formalin test, increased the hot plate threshold of normal mice, and down-regulated the expression of inflammatory cytokines in the spinal cord. Network analysis showed that Baimai Ointment had synergistic effect in the treatment of CCD and was related to descending inhibition/facilitation system and neuroinflammation. Furthermore, behavioral tests, Western blot, and immunofluorescence assay revealed that the pain-relieving effect of Baimai Ointment on CCD may be related to the regulation of the interaction between neuroactive ligand and receptors(neuroligands) such as CHRNA7, ADRA2A, and ADRB2, and the down-regulation of the expression of NOS2/pERK/PI3K, the core regulatory element of HIF-1 signaling pathway in spinal microglia. The findings preliminarily reveal the mechanism of relaxing sinew and activating collaterals of Baimai Ointment in the treatment of Baimai disease, providing a reference for the rational drug use and further research of this agent.
Rats ; Mice ; Animals ; Chronic Pain/metabolism* ; Rats, Sprague-Dawley ; Ganglia, Spinal/metabolism* ; Ligands ; Signal Transduction ; Hyperalgesia/metabolism* ; Drugs, Chinese Herbal

The animal models used in the experimental research of Traditional Chinese Medicine (TCM) to prevent and treat T2DM are mainly spontaneous and induced. The experimental research of TCM in the prevention and treatment of type 2 diabetes can be divided into Chinese medicine compound, Chinese medicine and its extract, Chinese medicine monomer. The mechanism is mainly through regulating intestinal flora, increasing insulin content, lowering blood sugar, lowering blood lipids, improving glucose tolerance, and improving gluconeogenesis, antioxidant, inhibit cell apoptosis, etc. play the role of preventing and treating T2DM in multiple links and multiple targets.

Objective:To analyze the characteristics of malaria epidemic situation before and after malaria elimination in Qiandongnan Prefecture, and to provide the basis for establishment of effective strategies and measures to consolidate the achievements of malaria prevention and control.Methods:The data of malaria cases in 16 counties (cities) of Qiandongnan Prefecture from 2005 to 2018 were collected, and descriptive epidemiological method was used to analyze the infection rate of Plasmodium among local residents and floating population before (2005-2011) and after (2012-2018) elimination of malaria, and the characteristics of population distribution, seasonal distribution, species of Plasmodium and types of malaria vectors were analyzed. Results:Before elimination of malaria, total of 1 412 cases of malaria were reported, among those cases, 1 361 cases were local cases, accounting for 96.39% of the total cases. After elimination of malaria, total of 17 cases were reported, all of them were imported cases. After comparison of malaria cases before and after the elimination, the proportion of people aged from 18 to 60 was 70.54% (996/1 412) before the elimination, all 17 imported cases were 18-60 years old after the elimination, and the proportion of children/students decreased from 24.65% (348/1 412) before the elimination to 0 after the elimination. The peak incidence of malaria cases before the elimination was from June to October, and cases occurred every month. After the elimination, the imported cases were sporadic. Plasmodium vivax was the main species of Plasmodium before the elimination (98.58%, 1 392/1 412), and Plasmodium falciparum was mainly imported after the elimination (70.59%, 12/17). Before and after the elimination, Anopheles sinensis, the malaria vector, was the dominant population, but no distribution of Anopheles minimus and Anopheles anthropophagus was found after 2015. Conclusions:After the elimination of malaria in Qiandongnan Prefecture, there is a risk of local malaria cases caused by imported cases. It is suggested that local authorities should focus on the treatment of suspected malaria cases and vector surveillance of overseas returnees in the future.

By reviewing the 2015 edition of Chinese Pharmacopoeia, the author collected 37 neutral blood-activating and stasis-removing traditional Chinese medicines. And by retrieving literatures on relevant material basis and pharmacological effects on CNKI, the author organized and summarized their chemical composition and pharmacological effects. Neutral blood-activating and stasis-removing traditional Chinese medicines are rich in chemical components, such as flavonoids, steroids and sugars. At the same time, it has a variety of pharmacological effects, including anti-platelet aggregation and anti-thrombotic mechanism, anti-atherosclerosis, inhibition of ischemia-perfusion injury, anti-tumor, anti-fibrosis, liver protection, anti-inflammatory analgesia, blood pressure reduction and immune regulation. It is widely used in the treatment of liver fibrosis, cardiovascular disease, liver cancer, uterine cancer, hypertension, hyperlipidemia and other diseases. Nowadays, as people has paid increasing attention to neutral herbs, studies on traditional Chinese medicines for activating blood circulation and removing blood stasis have been further deepened, which provides a better development prospect for neutral blood-activating and stasis-removing traditional Chinese medicines. From the perspective of medicinal properties, the authors systematically collected and summarized the pharmacological effects and material basis of neutral blood-activating and stasis-removing traditional Chinese medicines. This article provides theoretical guidance for the clinical application of neutral blood-activating and stasis-removing traditional Chinese medicines and new medicine research ideas for neutral blood-activating and stasis-removing traditional Chinese medicines.