GPR126, also known as ADGRG6, is one of the most deeply studied aGPCRs. Initially, GPR126 was thought to be a receptor associated with muscle development and was primarily expressed in the muscular and skeletal systems. With the deepening of research, it was found that GPR126 is expressed in multiple mammalian tissues and organs, and is involved in many biological processes such as embryonic development, nervous system development, and extracellular matrix interactions. Compared with other aGPCRs proteins, GPR126 has a longer N-terminal domain, which can bind to ligands one-to-one and one-to-many. Its N-terminus contains five domains, a CUB (complement C1r/C1s, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a SEA (Sperm protein, Enterokinase, and Agrin) domain, a hormone binding (HormR) domain, and a conserved GAIN domain. The GAIN domain has a self-shearing function, which is essential for the maturation, stability, transport and function of aGPCRs. Different SEA domains constitute different GPR126 isomers, which can regulate the activation and closure of downstream signaling pathways through conformational changes. GPR126 has a typical aGPCRs seven-transmembrane helical structure, which can be coupled to Gs and Gi, causing cAMP to up- or down-regulation, mediating transmembrane signaling and participating in the regulation of cell proliferation, differentiation and migration. GPR126 is activated in a tethered-stalk peptide agonism or orthosteric agonism, which is mainly manifested by self-proteolysis or conformational changes in the GAIN domain, which mediates the rapid activation or closure of downstream pathways by tethered agonists. In addition to the tethered short stem peptide activation mode, GPR126 also has another allosteric agonism or tunable agonism mode, which is specifically expressed as the GAIN domain does not have self-shearing function in the physiological state, NTF and CTF always maintain the binding state, and the NTF binds to the ligand to cause conformational changes of the receptor, which somehow transmits signals to the GAIN domain in a spatial structure. The GAIN domain can cause the 7TM domain to produce an activated or inhibited signal for signal transduction, For example, type IV collagen interacts with the CUB and PTX domains of GPR126 to activate GPR126 downstream signal transduction. GPR126 has homology of 51.6%-86.9% among different species, with 10 conserved regions between different species, which can be traced back to the oldest metazoans as well as unicellular animals.In terms of diseases, GPR126 dysfunction involves the pathological process of bone, myelin, embryo and other related diseases, and is also closely related to the occurrence and development of malignant tumors such as breast cancer and colon cancer. However, the biological function of GPR126 in various diseases and its potential as a therapeutic target still needs further research. This paper focuses on the structure, interspecies differences and conservatism, signal transduction and biological functions of GPR126, which provides ideas and references for future research on GPR126.

AIM To study the chemical constituents from the leaves of Cyanocarya paliurus(Batalin)Iljinskaja and their α-glucosidase inhibitory activities.METHODS The 95%ethanol extract from the leaves of C.paliurus was isolated and purified by macroporous resin,silica gel,Sephadex LH-20,polyamide,C18 reversed-phase silica gel and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.Their α-glucosidase inhibitory activities were evaluated by PNPG.RESULTS Fifteen compounds were isolated and identified as cyclopaloside C(1),cyclopaloside A(2),juglanosides E(3),vaccinin A(4),ent-murin A(5),kaempferol 3-O-α-L-rhamnopyranoside(6),kaempferol-3-O-β-D-glucopyranoside(7),kaempferol-3-O-β-D-glucuronide methyl ester(8),kaempferol-3-O-β-D-glucuronide ethyl ester(9),kaempferol-3-O-β-D-glucuronide butyl ester(10),quercetin-3-O-α-L-rhamnopyranoside(11)quercetin-3-O-β-D-glucopyranoside(12),quercetin-3-O-β-D-galactopyranoside(13),quercetin-3-O-β-D-glucuronide butyl ester(14),dihydrokaempferol(15).The IC50 value of total extracts ihibited α-glucosidase was(1.83±0.04)μg/mL,and the IC50 values of compounds 1,4-5 were(29.48±1.86),(0.50±0.07),(0.71±0.07)μmol/L,respectively.CONCLUSION Compound 1 is a new tetrahydronaphthalene glycoside.Compounds 4-5,8-10 and 14 are isolated from the leaves of C.paliurus for the first time.Compounds 4-5 are relatively rare flavonoid lignans with potential inhibitory activities against α-glucosidase.

Refractory depression is a drug-resistant subtype of major depressive disorder for which there is a lack of effective and durable treatments.Seroxibine,the active substance in the mushroom Capsicum annuum,is a natural 5-hydroxytryptamine hallucinogen that activates the 5-hydroxytryptamine 2A receptor to mediate multiple aspects of antidepressant effects.In recent years,it has received renewed attention for its outstanding therapeutic effects in the treatment of refractory depression or other psychiatric disorders.Therefore,this paper summarizes the studies on neuroplasticity,brain neural connectivity network,neurotransmitters,immune factors,microbiota-gut-brain axis,and clinical efficacy of seloxipine in domestic and international literature,and explores the possible mechanisms of seloxipine's effect on refractory depression,with a view to providing theoretical basis for the clinical application of this drug.

BACKGROUND: Butylphthalide (NBP) and edaravone (EDV) injection are common acute ischemic stroke medications in China, but there is a lack of large real-world safety studies on them. This study aimed to determine the incidence of adverse events, detect relevant safety signals, and assess the risk factors associated with these medications in real-world populations. METHODS: In this study, data of acute ischemic stroke patients were extracted from the electronic medical record database of six tertiary hospitals between January 2019 and August 2021. Baseline confounders were eliminated using propensity score matching. The drugs' safety was estimated by comparing the results of 24 laboratory tests standards on liver function, kidney function, lipid level, and coagulation function. The drugs' relative risk was estimated by logistic regression. A third group with patients who did not receive NBP or EDV was constructed as a reference. Prescription sequence symmetry analysis was used to evaluate the associations between adverse events and NBP and EDV, respectively. RESULTS: 81,292 patients were included in this study. After propensity score matching, the NBP, EDV, and third groups with 727 patients in each group. Among the 15 test items, the incidence of adverse events was lower in the NBP group than in the EDV group, and the differences were statistically significant. The multivariate logistic regression equation revealed that NBP injection was not a promoting factor for abnormal laboratory test results, whereas EDV had statistically significant effects on aspartate transaminase, low-density lipoprotein cholesterol and total cholesterol. Prescription sequence symmetry analysis showed that NBP had a weak correlation with abnormal platelet count. EDV had a positive signal associated with abnormal results in gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and platelet count. CONCLUSIONS In a large real-world population, NBP has a lower incidence of adverse events and a better safety profile than EDV or other usual medications.

Objective: To investigate the characteristics of pharmacokinetic (PK) and pharmacodynamic (PD) parameters of antibacterial agents in children with sepsis treated by extracorporeal membrane oxygenation (ECMO). Methods: In this prospective cohort study, 20 children with sepsis (confirmed or suspected) who were treated with ECMO and antimicrobial in the Department of Critical Medicine of Hunan Children's Hospital from March 2021 to December 2022 were enrolled as the ECMO group. Through therapeutic drug monitoring (TDM), the PK-PD parameters of antibacterial agents were analyzed. Twenty five children with sepsis in the same department who were treated with vancomycin but no ECMO at the same time were enrolled as the control group. The individual PK parameters of vancomycin were calculated by Bayesian feedback method. The PK parameters in the two groups were compared, and the correlation between trough concentration and area under the curve (AUC) was analyzed. Wilcoxon rank sum test was used for inter group comparison. Results: Twenty patients in the ECMO group, included 6 males and 14 females, with an onset age of 47 (9, 76) months. In the ECMO group, 12 children (60%) were treated with vancomycin, and the trough concentration was less than 10 mg/L in 7 cases, 10-20 mg/L in 3 cases, and >20 mg/L in 2 cases; AUC/minimum inhibitory concentration (MIC) (MIC=1 mg/L)<400 was in 1 case, 400-600 in 3 cases, and >600 in 8 cases. Among the 11 children (55%) who were treated with β-lactam antibiotics, there were 10 cases with drug concentration at 50% dosing interval (C_T50)>4 MIC and 9 cases with trough concentration>MIC, both C_T50 and trough concentration of cefoperazone reached the target. Among the 25 cases of control group, 16 were males and 9 females, with an onset age of 12 (8, 32) months. There was a positive correlation between vancomycin trough concentration and AUC (r²=0.36, P<0.001). The half-life of vancomycin and the 24-hour AUC (AUC_{0-24 h}) in the ECMO group were higher than those in the control group (5.3 (3.6, 6.8) vs. 1.9 (1.5, 2.9) h, and 685 (505, 1 227) vs. 261 (210, 355) mg·h/L, Z=2.99, 3.50, respectively; both P<0.05), and the elimination rate constant and clearance rate was lower than those in the control group (0.1 (0.1, 0.2) vs. 0.4 (0.2, 0.5), 0.7 (0.5, 1.3) vs. 2.0 (1.1, 2.8) L/h, Z=2.99, 2.11, respectively; both P<0.05). Conclusion: The PK-PD parameters in septic children treated by ECMO varied with a longer half-life, higher AUC_{0-24 h}, lower elimination rate constant and clearance rate.
Female ; Male ; Humans ; Child ; Child, Preschool ; Infant ; Anti-Bacterial Agents/therapeutic use* ; Vancomycin/therapeutic use* ; Bayes Theorem ; Extracorporeal Membrane Oxygenation ; Prospective Studies ; Sepsis/drug therapy*

Background::Exercise, as the cornerstone of pulmonary rehabilitation, is recommended to chronic obstructive pulmonary disease (COPD) patients. The underlying molecular basis and metabolic process were not fully elucidated.Methods::Sprague-Dawley rats were classified into five groups: non-COPD/rest ( n = 8), non-COPD/exercise ( n = 7), COPD/rest ( n = 7), COPD/medium exercise ( n = 10), and COPD/intensive exercise ( n = 10). COPD animals were exposed to cigarette smoke and lipopolysaccharide instillation for 90 days, while the non-COPD control animals were exposed to room air. Non-COPD/exercise and COPD/medium exercise animals were trained on a treadmill at a decline of 5° and a speed of 15 m/min while animals in the COPD/intensive exercise group were trained at a decline of 5° and a speed of 18 m/min. After eight weeks of exercise/rest, we used ultrasonography, immunohistochemistry, transmission electron microscopy, oxidative capacity of mitochondria, airflow-assisted desorption electrospray ionization-mass spectrometry imaging (AFADESI-MSI), and transcriptomics analyses to assess rectal femoris (RF). Results::At the end of 90 days, COPD rats’ weight gain was smaller than control by 59.48 ± 15.33 g ( P = 0.0005). The oxidative muscle fibers proportion was lower ( P < 0.0001). At the end of additional eight weeks of exercise/rest, compared to COPD/rest, COPD/medium exercise group showed advantages in weight gain, femoral artery peak flow velocity (Δ58.22 mm/s, 95% CI: 13.85-102.60 mm/s, P = 0.0104), RF diameters (Δ0.16 mm, 95% CI: 0.04-0.28 mm, P = 0.0093), myofibrils diameter (Δ0.06 μm, 95% CI: 0.02-0.10 μm, P = 0.006), oxidative muscle fiber percentage (Δ4.84%, 95% CI: 0.15-9.53%, P = 0.0434), mitochondria oxidative phosphorylate capacity ( P < 0.0001). Biomolecules spatial distribution in situ and bioinformatic analyses of transcriptomics suggested COPD-related alteration in metabolites and gene expression, which can be impacted by exercise. Conclusion::COPD rat model had multi-level structure and function impairment, which can be mitigated by exercise.

ObjectiveTo investigate the nephroprotective and anti-inflammatory effects of Fufang Shelong capsules （FFSL） in rats with membranous nephropathy （MN）， and the role of the p38 mitogen-activated protein kinase （MAPK） signaling pathway. MethodMale SD rats of SPF grade were divided into a normal group and an experimental group. The MN model was induced by tail vein injection of cationized bovine serum albumin in the experimental group. After screening， the eligible model rats were included and divided into a positive control group （tripterygium glycosides tablets） and low-， medium-， and high-dose FFSL groups （0.375， 0.75， 1.5g·kg^-1）. The rats were treated correspondingly for eight weeks， and urine protein was detected during drug intervention. Renal function and inflammation-related indicators were detected after drug intervention. The changes in 24-hour urine total protein （24 h UP）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， tumor necrosis factor-α （TNF-α）， creatinine （Cr）， blood urea nitrogen （BUN）， total protein （TP）， albumin （Alb）， and total cholesterol （TC） were detected. Flow cytometry was used to detect CD4⁺/CD8⁺ changes. Kidney tissues were collected to observe pathological changes under a light microscope and an electron microscope. The protein expression of p38 MAPK and phosphorylated p38 MAPK （p-p38 MAPK） in kidney tissues was detected by Western blot. ResultCompared with the normal group， the model group showed increased 24 h UP （P<0.01）， elevated serum Cr， BUN， TC， IL-6， IL-8， and TNF-α （P<0.05，P<0.01）， decreased serum Alb and TP levels （P<0.05，P<0.01）， increased CD4⁺/CD8⁺ in the peripheral blood （P<0.01）， and up-regulated protein expression of p38 MAPK and p-p38 MAPK in kidney tissues （P<0.05）. Additionally， in the model group， immune complex deposition and foot process fusion， accompanied by infiltration of inflammatory cells， were observed on the epithelial side of the basement membrane in the pathological kidney tissues. Compared with the model group， the groups with drug intervention showed declining 24 h UP levels at six weeks （P<0.05，P<0.01）， decreased serum Cr， BUN， TC， IL-6， IL-8， and TNF-α （P<0.05，P<0.01）， increased serum Alb and TP levels （P<0.05，P<0.01）， reduced CD4⁺/CD8⁺ in the peripheral blood （P<0.01）， improved renal pathological damage， and down-regulated p38 MAPK and p-p38 MAPK in kidney tissues （P<0.05，P<0.01）. ConclusionFFSL can decrease the expression of inflammatory factors， reduce proteinuria， delay kidney damage， and protect kidney function by inhibiting the expression of the p38 MAPK signaling pathway.

ObjectiveTo explore the potential anti-tuberculosis mechanism of Kanglao granule through network pharmacology. MethodThe active components of Kanglao granule were retrieved from related databases and the potential targets of the components from SwissTargetPrediction. Targets of the tuberculosis were screened from GeneCards and National Center for Biotechnology Information （NCBI）， and the anti-tuberculosis targets of the prescription were further identified. STRING and Cytoscape 3.8.0 were employed to construct the Chinese medicinal-disease target-signaling pathway network and screen core targets. Then gene ontology （GO） term enrichment and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment were performed. Finally， AutoDock Vina was used for molecular docking between the active components of the prescription and key proteins and Western blotting for verifying the interaction between them. ResultA total of 29 important chemical components in the prescription were screened out， including β-sitosterol， sesamin， and kaempferol. A total of 28 key anti-tuberculosis targets were retrieved， such as protein kinase B1 （Akt1）， epidermal growth factor receptor （EGFR）， hypoxia inducible factor-1A （HIF-1A）， proto-oncogene tyrosine-protein kinase （SRC）， and matrix metalloproteinase-9 （MMP-9）. Bioinformatics analysis showed the 28 targets were involved in 41 GO terms such as oxygen metabolism， nucleic acid transcription， and metabolic enzyme pathway， and 28 key KEGG pathways， including Mycobacterium tuberculosis signaling pathway and phosphatidylinositol 3 kinase/protein kinase B pathway. Molecular docking results showed that Akt1 had the strongest binding affinity to sesamin. In vitro experiment indicated that sesamin inhibited the growth of M. tuberculosis by suppressing the phosphorylation of Akt1. ConclusionKanglao granule improved the sterilization level and immune response through multi-component， multi-target， and multi-pathway interactions， thereby achieving therapeutic effect on tuberculosis. Akt1 is one of the important targets involved in the treatment of tuberculosis.

AIM: To observe the clinical effect of posterior chamber phakic refractive lens(PC-PRL)implantation in the treatment of ultra-high myopia.METHODS: Retrospective case study. A total of 36 patients(67 eyes)with ultra-high myopia who underwent PC-PRL implantation in our hospital from January 2021 to January 2022 were selected. They were and divided into two groups according to the preoperative spherical equivalent, with 16 cases(30 eyes)in spherical equivalent ≤-18.00D group and 20 cases(37 eyes)in spherical equivalent >-18.00D group. The preoperative and postoperative visual acuity, intraocular pressure(IOP), corneal endothelial cell density(ECD), central anterior chamber depth(ACD)and postoperative vault and complications were compared and analyzed.RESULTS: The uncorrected visual acuity(UCVA)at 3mo after operation of the two groups reached or exceeded the preoperative best corrected visual acuity(BCVA; all P<0.05), and the spherical equivalent >-18.00D group had a greater visual acuity improvement(P<0.01). There were significant differences in IOP and corneal ECD between the two groups at 1d after operation and before operation(all P<0.05); The vault at different time points decreased after operation, but it was within the normal range; The ACD at 3mo after operation was lower than that before operation(all P<0.01). There was no difference in intraocular pressure, ECD, ACD and postoperative vault between the two groups(P>0.05). No serious postoperative complications occurred in both groups.CONCLUSION: The PC-PRL implantation had improved early visual acuity and stable refractive state, which was safe and reliable, and there were no serious complications in the treatment of patients with ultra-high myopia.

Objective: To estimate the incidence of HIV-1 infection in men who have sex with men (MSM) in key areas of China through HIV-1 limiting antigen avidity enzyme immunoassay (LAg-Avidity EIA), analyze the deviation from the actual results and identify influencing factors, and provided reference for improving the accuracy of estimation results. Methods: Based on the principle of the cohort randomized study design, 20 cities were selected in China based on population size and the number of HIV-positive MSM. The sample size was estimated to be 700 according to the HIV-1 infection rate in MSM. MSM mobile phone app. was used to establish a detection appointment and questionnaire system, and the baseline cross-sectional survey was conducted from April to November 2019. LAg-Avidity EIA was used to identify the recent infected samples. The incidence of HIV-1 infection was calculated and then adjusted based on the estimation formula designed by WHO. The influencing factors were identified by analyzing the sample collection and detection processes. Results: Among the 10 650 blood samples from the participants, 799 were HIV-positive in initial screening, in which 198 samples (24.78%) missed during confirmation test. Only 621 samples were received by the laboratory. After excluding misreported samples, 520 samples were qualified for testing. A total of 155 samples were eventually determined as recent infection through LAg-Avidity EIA; Based on the estimation formula , the incidence of HIV-1 infection in MSM in 20 cities was 4.06% (95%CI:3.27%-4.85%), it increased to 5.53% (95%CI: 4.45%-6.60%)after the adjusting for sample missing rate. When the sample missing rate and misreporting rate were both adjusted, the incidence of HIV-1 infection in the MSM increased to 5.66% (95%CI:4.67%-6.65%). The actual incidence of HIV-1 infection in MSM in the 20 cities might be between 4.06% and 5.66%. Conclusions: Sample missing and misreporting might cause the deviation of the estimation of HIV-1 infection incidence. It is important to ensure the sample source and the quality of sample collection and detection to reduce the deviation in the estimation of HIV-1 infection incidence.
Cross-Sectional Studies ; HIV Infections/epidemiology* ; HIV-1 ; Homosexuality, Male ; Humans ; Immunoenzyme Techniques ; Incidence ; Male ; Sexual and Gender Minorities