“Runner’s high” refers to a momentary sense of pleasure that suddenly appears during running or other exercise activities, characterized by anti-anxiety, pain relief, and other symptoms. The neurobiological mechanism of “runner’s high” is unclear. This review summarizes human and animal models for studying “runner’s high”, analyzes the neurotransmitters and neural circuits involved in runner’s high, and elucidates the evidence and shortcomings of researches related to “runner’s high”. This review also provides prospects for future research. Research has found that exercise lasting more than 30 min and with an intensity exceeding 70% of the maximum heart rate can reach a “runner’s high”. Human experiments on “runner’s high” mostly use treadmill exercise intervention, and evaluate it through questionnaire surveys, measurement of plasma AEA, miRNA and other indicators. Animal experiments often use voluntary wheel running intervention, and evaluate it through behavioral experiments such as conditional place preference, light dark box experiments (anxiety), hot plate experiments (pain sensitivity), and measurement of plasma AEA and other indicators. Dopamine, endogenous opioid peptides, endogenous cannabinoids, brain-derived neurotrophic factor, and other substances increase after exercise, which may be related to the “runner’s high”. However, attention should be paid to the functional differences of these substances in the central and peripheral regions, as well as in different brain regions. Moreover, current studies have not identified the targets of the neurotransmitters or neural factors mentioned above, and further in-depth researches are needed. The mesolimbic dopamine system, prefrontal cortex-nucleus accumbens projection, ventral hippocampus-nucleus accumbens projection, red nucleus-ventral tegmental area projection, cerebellar-ventral tegmental area projection, and brain-gut axis may be involved in the regulation of runner’s high, but there is a lack of direct evidence to prove their involvement. There are still many issues that need to be addressed in the research on the neurobiological mechanisms of “runner’s high”. (1) Most studies on “runner’s high” involve one-time exercise, and the characteristics of changes in “runner’s high” during long-term exercise still need to be explored. (2) The using of scales to evaluate subjects lead to the lacking of objective indicators. However, some potential biomarkers (such as endocannabinoids) have inconsistent characteristics of changes after one-time and long-term exercise. (3) The neurotransmitters involved in the formation of the “runner’s high” all increase in the peripheral and/or central nervous system after exercise. Attention should be paid to whether peripheral substances can enter the blood-brain barrier and the binding effects of neurotransmitters to different receptors are completely different in different brain regions. (4) Most of the current evidence show that some brain regions are activated after exercise. Is there a functional circuit mediating “runner’s high” between these brain regions? (5) Although training at a specific exercise intensity can lead to “runner’s high”, most runners have not experienced “runner’s high”. Can more scientific training methods or technological means be used to make it easier for people to experience the “runner’s high” and thus be more willing to engage in exercise? (6) The “runner’s high” and “addiction” behaviors are extremely similar, and there are evidences that exercise can reverse addictive behaviors. However, why is there still a considerable number of people in the sports population and even athletes who smoke or use addictive drugs instead of pursuing the “pleasure” brought by exercise? Solving the problems above is of great significance for enhancing the desire of exercise, improving the clinical application of neurological and psychiatric diseases through exercise, and enhancing the overall physical fitness of the population.

ObjectiveBased on the phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， the effects of Huanglian Zhimutang on glucose and lipid metabolism disorders and hepatic insulin resistance （IR） with type 2 diabetes mellitus （T2DM） were investigated. MethodsGoto-Kakizaki （GK） rats were fed a high-fat diet to induce a T2DM rat model and then randomly divided into four groups： normal control group， model control group， metformin group （0.10 g·kg^-1）， and Huanglian Zhimutang group （3.60 g·kg^-1）， with eight rats in each group. Drug intervention was administered continuously for 8 weeks. Serum and liver tissues were collected from each group. Fasting insulin （FINS） levels were measured using enzyme-linked immunosorbent assay （ELISA）， and the homeostasis model assessment of insulin resistance （HOMA-IR） index was calculated. Total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， and high-density lipoprotein cholesterol （HDL-C） levels were measured using an automatic biochemical analyzer. Liver tissue pathology was observed via hematoxylin-eosin （HE） staining. Serum interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） levels were detected using ELISA. Network pharmacology and transcriptomics sequencing were combined to analyze differentially expressed genes （DEGs） in liver tissue from the normal control group， model control group， and Huanglian Zhimutang group. Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis was performed to identify pathways affected by Huanglian Zhimutang intervention in T2DM. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to assess the mRNA expression of insulin receptor substrate-1 （IRS-1）， PI3K， Akt， and peroxisome proliferator-activated receptor gamma （PPARγ） in liver tissue， while Western blot was used to evaluate corresponding protein expression levels. ResultsAfter 8 weeks of Huanglian Zhimutang intervention， typical symptoms of T2DM rats such as polydipsia， polyphagia， and polyuria were significantly alleviated， along with reductions in fasting blood glucose levels and insulin resistance（P<0.01）. Histopathological results revealed that Huanglian Zhimutang effectively improved hepatic steatosis and inflammatory edema and reduced lipid vacuole formation. Biochemical tests demonstrated that Huanglian Zhimutang significantly reduced serum levels of TC， TG， and LDL-C（P<0.01）. ELISA results showed that Huanglian Zhimutang effectively decreased serum concentrations of IL-6 and TNF-α（P<0.05，P<0.01）. Combined network pharmacology predictions with KEGG pathway analysis of transcriptomics showed that DEGs between the Huanglian Zhimutang and model control groups were significantly enriched in the PI3K/Akt signaling pathway. Real-time PCR and Western blot results confirmed that Huanglian Zhimutang upregulated the expression of PI3K/Akt signaling pathway-related mRNAs and proteins in liver tissue（P<0.05，P<0.01）， thereby reducing inflammation， alleviating hepatic lipid accumulation， and enhancing insulin sensitivity. ConclusionHuanglian Zhimutang effectively ameliorates glucose and lipid metabolism disorders in T2DM rats. Its mechanism may be related to the regulation of the PI3K/Akt pathway， which reduces inflammation and hepatic lipid deposition and relieves hepatic insulin resistance.

ObjectiveBased on the phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， the effects of Huanglian Zhimutang on glucose and lipid metabolism disorders and hepatic insulin resistance （IR） with type 2 diabetes mellitus （T2DM） were investigated. MethodsGoto-Kakizaki （GK） rats were fed a high-fat diet to induce a T2DM rat model and then randomly divided into four groups： normal control group， model control group， metformin group （0.10 g·kg^-1）， and Huanglian Zhimutang group （3.60 g·kg^-1）， with eight rats in each group. Drug intervention was administered continuously for 8 weeks. Serum and liver tissues were collected from each group. Fasting insulin （FINS） levels were measured using enzyme-linked immunosorbent assay （ELISA）， and the homeostasis model assessment of insulin resistance （HOMA-IR） index was calculated. Total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， and high-density lipoprotein cholesterol （HDL-C） levels were measured using an automatic biochemical analyzer. Liver tissue pathology was observed via hematoxylin-eosin （HE） staining. Serum interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） levels were detected using ELISA. Network pharmacology and transcriptomics sequencing were combined to analyze differentially expressed genes （DEGs） in liver tissue from the normal control group， model control group， and Huanglian Zhimutang group. Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis was performed to identify pathways affected by Huanglian Zhimutang intervention in T2DM. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to assess the mRNA expression of insulin receptor substrate-1 （IRS-1）， PI3K， Akt， and peroxisome proliferator-activated receptor gamma （PPARγ） in liver tissue， while Western blot was used to evaluate corresponding protein expression levels. ResultsAfter 8 weeks of Huanglian Zhimutang intervention， typical symptoms of T2DM rats such as polydipsia， polyphagia， and polyuria were significantly alleviated， along with reductions in fasting blood glucose levels and insulin resistance（P<0.01）. Histopathological results revealed that Huanglian Zhimutang effectively improved hepatic steatosis and inflammatory edema and reduced lipid vacuole formation. Biochemical tests demonstrated that Huanglian Zhimutang significantly reduced serum levels of TC， TG， and LDL-C（P<0.01）. ELISA results showed that Huanglian Zhimutang effectively decreased serum concentrations of IL-6 and TNF-α（P<0.05，P<0.01）. Combined network pharmacology predictions with KEGG pathway analysis of transcriptomics showed that DEGs between the Huanglian Zhimutang and model control groups were significantly enriched in the PI3K/Akt signaling pathway. Real-time PCR and Western blot results confirmed that Huanglian Zhimutang upregulated the expression of PI3K/Akt signaling pathway-related mRNAs and proteins in liver tissue（P<0.05，P<0.01）， thereby reducing inflammation， alleviating hepatic lipid accumulation， and enhancing insulin sensitivity. ConclusionHuanglian Zhimutang effectively ameliorates glucose and lipid metabolism disorders in T2DM rats. Its mechanism may be related to the regulation of the PI3K/Akt pathway， which reduces inflammation and hepatic lipid deposition and relieves hepatic insulin resistance.

Syk Kinase ; Tyrosine/metabolism* ; Phosphorylation

Aim To discover the potential active compounds and possible mechanisms in rheumatoid arthritis (RA) treatment with Zhi-Huang-Zhi-Tong powder (ZHZTP) by using network pharmacology and in vitro study. Methods The active ingredient targets and disease targets of Zhihuang Zhitong Powder were searched and screened by database; they intersected to get a common target; and the "drug-component-target" relationship network diagram was constructed for GO and KEGG enrichment analysis of the overlapping genes; then the core components were docked with the core targets. Finally, based on the inflammation model of HUVECs in vitro, the efficacy and mechanism of Zhihuang Zhitong powder were verified by MTT method, plate scratch test and Western blot. Results Active compounds involved in RA treatment were screened in the present study, and the top two were ursolic acid and emodin, all playing crucial roles in RA treatment with ZHZTP. Additionally, the key target was AKTA, TNF and IL-6. GO and KEGG enrichment analysis revealed that ZHZTP regulated BP, MF and CC, and also focused on regulating AKTA, TNF and IL-6 signaling pathway. Molecular docking showed that interactions between key active compounds and key targets were stable. In vitro ZHZTP significantly inhibited cell viability and migration of TNF-a-stimulated HUVECs, and the involved mechanism may be associated with PI3K/AKT/m-TOR signaling. Conclusions The present study reveals that the potential active compounds of ZHZTP are ursolic acid and emodin, and moreover, the involved mechanisms of ZHZTP for RA treatment are associated with PI3 K/AKT/m-TOR signaling.

Objective To explore the implementation effect of PDCA model in medical dispute legal risk management.Methods Conduct research on medical disputes,early warning,and disposal methods before and after PDCA cycle improvement(January 2022 to December 2022)and after PDCA cycle improvement(January 2023 to August 2023).Results Before imple-menting the PDCA model(2022),there were 2 cases(20.00％)of medical disputes among patients in thoracic surgery,head and neck surgery,oncology,and gynecology,as well as 1 case(10.00％)in the radiology group and 1 case(10.00％)in the early diagnosis of urban cancer.After implementing the PDCA model(2023),4 cases occurred and the incidence of medical dis-putes in relevant departments decreased(P＜0.05);There were 28 complaints before the implementation of the PDCA model(2022),and 7 after the implementation of the PDCA model(2023).There was a statistically significant difference(P＜0.05)in the reported departments of thoracic surgery,head and neck surgery,oncology,laboratory,and hospital epidemic prevention and control issues before and after management.Conclusion The PDCA model can improve the ability of medical dispute risk warning and resolution,as well as the quality of risk management work,reduce the incidence rate,and is worth promoting and applying.

Objective We aimed to evaluate the clinical efficacy of promoting blood circulation and eliminating phlegm method in preventing and treating patients with hydrocephalus after acute intracerebral hemorrhage.Methods This study included 139 patients with acute intracerebral hemorrhage who visited Affiliated Hospital of Chengdu University of Traditional Chinese Medicine,Guangyuan Hospital of Traditional Chinese Medicine,Affiliated Hospital of North Sichuan Medical College,Meishan Hospital of Traditional Chinese Medicine,and Xuyong Hospital of Traditional Chinese Medicine from September 2019 to June 2023.Patients who met the exposure factors of"using the method of promoting blood circulation and eliminating phlegm"were classified into the integrated Chinese and Western medicine cohort,while those who did not meet the exposure factors were classified into the Western medicine cohort.Clinical efficacy,incidence of hydrocephalus after intracerebral hemorrhage,sum of maximum distance between the anterior horn of the lateral ventricle and the head of the caudate nucleus(Huckman value),size of the hematoma,incidence of endpoint events,National Institutes of Health Stroke Scale(NIHSS)score,Modified Rankin Scale(mRS)score,and Barthel index score between two cohorts were compared.Results Total clinical effective rates for patients with hydrocephalus in the two cohorts were 60.0%and 75.0%,respectively.The total effective rate of the integrated Chinese and Western medicine cohort was higher than that of the Western medicine cohort(P<0.05).After 28 days of treatment,the incidence of hydrocephalus in patients in the integrated Chinese and Western medicine cohort was lower than that of the Western medicine cohort,and the Huckman value decreased compared with the Western medicine cohort(P<0.05).Compared with 24 hours after onset,both cohorts showed a reduction in hematoma size after 28 days of treatment;compared with the Western medicine cohort,patients in the integrated Chinese and Western medicine cohort had reduced hematoma size(P<0.05).After 6 months of onset,the number of deaths in the integrated Chinese and Western medicine cohort decreased compared with the Western medicine cohort(P<0.05).Compared with 28 days of treatment,the NIHSS and mRS scores of the patients in both cohorts decreased after 6 months,while the Barthel index score increased;compared with the Western medicine cohort,patients in the integrated Chinese and Western medicine cohort showed a decrease in the NIHSS and mRS scores after both 28 days of treatment and 6 months,while the Barthel index score increased(P<0.05).Conclusion Promoting blood circulation and eliminating phlegm can effectively prevent and treat hydrocephalus after intracerebral hemorrhage and does not increase the risk of bleeding within 24 hours.

Outer membrane vesicles (OMVs) are nanoscale vesicles secreted by Gram-negative bacteria. As a unique bacterial secretion, OMV secretion can help bacteria maintain the outer membrane stability or remove harmful substances. Studies have shown that local separation of outer membrane and peptidoglycan layers led by abnormalities in outer membrane protein function, abnormal structure or excessive accumulation of LPS, and erroneous accumulation of phospholipids in the outer leaflet, which can all lead to bacterial outer membrane protrusion and eventually bud formation of OMVs. Since OMVs are mainly composed of bacterial outer membrane and periplasmic components, the pathogen associated molecular patterns (PAMPs) on their surface can trigger strong immune responses. For example, OMVs can recruit and activate neutrophils, polarize macrophages to secrete large amounts of inflammatory factors. More importantly, OMVs can act as adjuvants to induce dendritic cell (DC) maturation to enhance adaptive immune response in the body. At the same time, OMVs are derived from bacteria, which make it easy to modify. The methods by genetic engineering and others can improve their tumor targeting, give them new functions, or reduce their immunotoxicity, which is conducive to their application in tumor therapy. OMVs not only induce apoptosis or pyroptosis of tumor cells, but also regulate the host immune system, which makes OMVs themselves have a certain killing effect on tumors. In addition, the tendency of neutrophils to inflammatory tumor sites and the formation of neutrophil extracellular traps enable OMVs to target tumor sites, and the suitable size and the characteristic that they are easily taken up by DCs give OMVs a certain lymphatic targeting ability. Therefore, OMVs are often employed as excellent drug or vaccine carriers in tumor therapy. This review mainly discusses the biological mechanism of OMVs, the regulatory effects of OMVs on immune cells, the functional modification strategies of OMVs, and their research progress in tumor therapy.

Objective To evaluate the bioequivalence of test product and reference product in a single dose of amoxicillin clavulanate potassium tablet under fasting and fed conditions in healthy volunteers.Methods An open label,randomized,single dose,four-period,crossover bioequivalence study was designed.Fasting and postprandial tests were randomly divided into 2 administration sequence groups according to 1:1 ratio,amoxicillin clavulanate potassium tablet test product or reference product 375 mg,oral administration separately,liquid chromatography tanden mass spectrometry was applied to determine the concentration of amoxicillin and clavulanate potassium in plasma of healthy subjects after fasting or fed administration,while Phoenix WinNonlin 8.2 software were used for pharmacokinetics(PK)parameters calculation and bioequivalence analysis.Results Healthy subjects took the test product and the reference product under fasting condition,the main PK parameters of amoxicillin are as follows:Cmax were(5 075.57±1 483.37)and(5 119.86±1 466.73)ng·mL-1,AUC0_twere(1.32 × 104±2 163.76)and(1.30 × 104±1 925.11)ng·mL-1,AUC0-∞were(1.32 × 104±2 175.40)and(1.31 ×104±1 935.86)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(3 298.27±1 315.23)and(3 264.06±1 492.82)ng·mL-1,AUC0-twere(7 690.06±3 053.40)and(7 538.39±3 155.89)ng·mL-1,AUC0-∞were(7 834.81±3 082.61)and(7 671.67±3 189.31)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-tand AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Healthy subjects took the test and reference product under fed condition,the main PK parameters of amoxicillin are as follows:Cmax were(4 514.08±1 324.18)and(4 602.82±1 366.48)ng·mL-1,AUC0-twere(1.15 × 104±1 637.95)and(1.15 × 104±1 665.69)ng·mL-1,AUC0-∞ were(1.16 × 104±1 646.26)and(1.15 × 104±1 607.20)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(2 654.75±1 358.29)and(2 850.51±1 526.31)ng·mL-1,AUC0-twere(5 882.82±2 930.06)and(6 161.28±3 263.20)ng·mL-1,AUC0-∞ were(6 022.70±2 965.05)and(6 298.31±3 287.63)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-t and AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Conclusion The two formulations were bioequivalent to healthy adult volunteers under fasting and fed conditions.

Background Self-perceived burden,anxiety and depression are among the most important factors affecting quality of life.At present,there is a lack of understanding on the research status and influencing factors of self-perceived burden in liver transplant recipients.Previous studies have shown that self-perceived burden,anxiety,depression and quality of life are correlated in pairs,but the effecting path among the three are not yet clear.Objective To explore the correlation of self-perceived burden and anxiety/depression with quality of life in liver transplant recipients,so as to provide guidance for psychological nursing intervention in clinical patients.Methods A total of 200 patients liver transplant recipients were enrolled from the liver transplantation inpatient and outpatient clinics of Jiangsu Province Hospital and Qinhuai Medical Area,General Hosptial of Eastern Theater Command of People's Liberation Army of China from March 2022 to February 2023.Patients were evaluated using Self-perceived Burden Scale(SPBS),Hospital Anxiety and Depression Scale(HADS)and the Chinese version of Post Liver Transplant Quality of Life Questionnaire(pLTQ).Spearman correlation analysis was used to examine the correlation among the scales.A structural equation model using Mplus 8.3 was utilized to testify the relationship among self-perceived burden,anxiety/depression and quality of life in liver transplant recipients.Bootstrap method was used to test the effecting pathway.Results There were statistically significant differences in SPBS scores of liver transplant recipients with different levels of education and fannual family income(H=9.656,18.796,P<0.05).There were statistically significant differences in HADS scores of liver transplant recipients with different numbers of somatic symptoms(H=9.859,P<0.05).There were statistically significant differences in the Chinese version of pLTQ scores of liver transplant recipients with different levels of education,postoperative survival time and numbers of somatic symptoms(H=6.892,8.023,16.099,P<0.05).The total and each dimension scores in SPBS of liver transplant recipients were positively correlated with the total score and anxiety/depression dimension scores in HADS(r=0.464～0.586,0.460～0.593,0.286～0.408,0.464～0.583,P<0.01)and negatively correlated with the total score and each dimension scores in the Chinese version of pLTQ(r=-0.572～-0.416,-0.599～-0.441,-0.365～-0.213,-0.559～-0.428,P<0.01).Structural equation model denoted that self-perceived burden negatively affected quality of life(β=-0.186,P<0.01).Anxiety/depression also negatively affected quality of life(β=-0.679,P<0.01).The self-perceived burden indirectly affected the quality of life of liver transplant recipients through anxiety and depression,with an effect value of-0.429,accounting for 69.76％of the total effect.Conclusion The quality of life in liver transplant recipients may be related to their self-perceived burden and anxiety/depression.Self-perceived burden may affect the quality of life of liver transplant patients through anxiety and depression.