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.

Objective To explore the potential mechanisms of hypoxic adaptive metabolic changes in the kidneys of plateau pikas at different altitudes using non-targeted metabolomics analysis via ultra-high-performance liquid chromatography coupled with quadrupole electrostatic field orbital trap-mass spectrometry (UHPLC-QE-MS). Methods 10 plateau pikas were captured at an altitude of 4 360 m in Xingxiuhai area, Maduo County, Guoluo Tibetan Autonomous Prefecture, Qinghai Province (MD group), and 10 plateau pikas were captured at an altitude of 2 900 m in Menyuan area, Haibei Tibetan Autonomous Prefecture, Qinghai Province (MY group). After anesthesia, serum samples were collected, and kidney samples were collected after euthanasia. General physiological and biochemical indicators were measured and metabolomics analysis was performed. Part of the serum samples was used for hematology analysis, another part for blood gas analysis, and the remaining part for biochemical indicator detection. Metabolites were extracted from the kidney tissue samples and then analyzed using UHPLC-QE-MS. Differential metabolites were analyzed using metabolomics principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), with screening criteria set as variable importance in projection (VIP)>1.5 and fold change (FC)>1.5, or VIP>1.5 and FC<1/1.5. Correlation analysis heatmaps, significance analysis volcano plots, signaling pathway recognition bubble charts, and rectangular graphs were used for the analysis of differential metabolites and related signaling pathways. Results The red blood cell count, glucose, urea nitrogen, uric acid, and homocysteine levels in the MD group plateau pikas were higher than those in the MY group, while hemoglobin, hematocrit, creatinine, and carbon dioxide combining power were lower than those in the MY group. This indicated a significant difference in the blood oxygen-carrying capacity of plateau pikas at different altitudes. The principal component pattern recognition analyses, and OPLS-DA permutation test showed that the kidney metabolites of the MD and MY groups of plateau pikas had distinct clustering distributions (R²Y=0.930, Q²=0.655). According to the screening criteria and database comparison, 46 differential metabolites were identified in the kidneys of plateau pikas at different altitudes. In the MD group of plateau pikas, the expression levels of bufadienolide, adenosine, adenine, diosgenin, berberine chloride, carnosol, and astaxanthin were significantly increased (VIP>1.5, P<0.05), while the levels of arachidonic acid, histamine, and coumarin were significantly decreased (VIP>1.5, P<0.05). The analysis of related signaling pathways showed that the biosynthetic pathways of valine, leucine, and isoleucine had the largest impact factors (P<0.05), while the biosynthetic pathways of pantothenate and coenzyme A showed the most significant enrichment (P<0.05). Conclusion The differential metabolites of amino acids, pantothenate, and coenzyme A pathways in the kidneys of plateau pikas at different altitudes may be involved in the metabolic mechanisms of plateau pikas' hypoxia adaptation in high-altitude environments.

Based on the traditional Chinese medicine theory that "all pain， itching， and sores are related to the heart"， this paper proposes treating recurrent aphthous ulcers from the perspective of the heart. It suggests that excessive heart fire and tissue erosion due to flaming fire in the heart meridian constitute the core pathogenesis of this condition. Hyperactive heart fire is identified as the key pathogenic factor， while heart yin deficiency， obstruction of the heart collaterals， and malnourishment of the heart spirit are considered significant contributing factors. Clinically， the treatment follows the principle of clearing heart fire as the main strategy， supplemented by nourishing yin， activating collaterals， and calming the spirit. The self-formulated Qingxin Yuchuang Formulation （清心愈疮方） serves as the base prescription， with flexible modifications incorporating the Yuyin Formulation （育阴方）， Huoxue Formulation （活血方）， and Yu'an Formulation （郁安方） to address specific syndromes involving heart yin deficiency， collateral blockage， and emotional disturbance.

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.

OBJECTIVE To provide reference for improving the level of hospital pharmaceutical management for operating room drugs. METHODS The operating room pharmacy of our hospital utilized the concept and means of the Internet of Things （IoT） to build an intelligent IoT system for operating room drugs （hereinafter referred to as the “IoT system”）， and optimized and improved it. The quality of drug management in the operating room of our hospital during the initial phase of the IoT system （Q1 2022） and after optimization and improvement （Q1 2023） were compared by setting indicators from four aspects： quality， efficiency， cost， and satisfaction. RESULTS After more than a year of optimization and improvement， our hospital has built a traceable IoT system for the entire drug process that integrated surgical anesthesia systems and hospital information systems， with the direction of drug circulation in the operating room as the axis， using intelligent drug vehicles as the hardware foundation， and anesthesia doctor’s order information system as the software medium. After the optimization and improvement of the IoT system， the standardized score of anesthesia orders in the operating room increased from （68.5±3.5） points in the initial period to （97.0± 2.7） points； the consistency rate between accounts and materials increased from （82.40±8.85）% to （96.50±4.80）%； the time of taking medicine was shortened from （40±8） min to （12±3） min； the frequency of drug withdrawal was reduced from （36.0± 6.5） times/day to （15.5±3.0） times/day； the cost of loss drugs was decreased from （1 292.61±305.90） yuan to （594.24±195.05） yuan； the satisfaction was increased from （80.5±6.5） points to （96.0±3.0） points. All indicators were significantly improved with statistically significant differences （P＜0.05）. CONCLUSIONS The intelligent IoT system constructed by our hospital effectively ensures the accessibility， timeliness， and safety of intraoperative medication， which is conducive to improving the quality of drug management in the operating room.

Objective:To explore the evaluation value of serum levels of positive pentameric protein 3 (PTX3) and creatine kinase isoenzyme MB (CK-MB) on volume load in patients with chronic decompensated heart failure (CDHF).Methods:A total of 300 CDHF patients who visited the Xingtai Central Hospital from July 2019 to July 2022 were selected and divided into a capacity overload group ( n=182) and a non capacity overload group ( n=118) based on their capacity balance level. Two clinical data sets were compared and analyzed. The receiver operating characteristic (ROC) curve was used to analyze the evaluation value of serum PTX3 and CK-MB levels on the volume load of CDHF patients. The clinical disease characteristics of the two groups of patients were analyzed using univariate analysis, and the influencing factors of volume load of CDHF patients were analyzed using logistic regression. A column chart model was constructed and validated. Results:The body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose (FBG), glycosylated hemoglobin (HbA 1c), C-reactive protein (CRP), uric acid (UA), homeostasis model assessment of insulin resistance (HOMA-IR) of patients in the capacity overload group were higher than those in the non-capacity overload group, and the differences were statistically significant (all P<0.05). The PTX3, CK-MB, pulmonary capillary wedge pressure (PCWP), and CVP levels of patients in the capacity overload group were higher than those in the non-capacity overload group, while albumin, hemoglobin, and hematocrit were lower than those in the non-capacity overload group, and the differences were statistically significant (all P<0.05). The ROC curve showed that the area under the curve (AUC) of PTX3 and CK-MB for predicting capacity overload in CDHF patients are 0.795 and 0.718, with sensitivity of 86.2% and 83.7%, specificity of 65.4% and 68.6%, respectively, indicating high predictive accuracy; The AUC of the two joint predictions is 0.817, the sensitivity was 92.5%, and the specificity was 70.6%. The prediction accuracy was higher than PTX3 ( Z=3.812, P<0.05) and CK-MB ( Z=3.365, P<0.05). PTX3, CK-MB, albumin, hemoglobin, hematocrit, PCWP, and central venous pressure (CVP) were all influencing factors of volume load status in CDHF patients (all P<0.05). The column chart risk prediction model established based on these factors had high accuracy and strong applicability in clinical treatment. Conclusions:Serum PTX3 and CK-MB levels are influencing factors for volume overload in CDHF patients. A column chart model constructed in combination with indicators such as albumin, hemoglobin, hematocrit, PCWP, and CVP has high predictive value for the volume overload status of CDHF.

Objective:To explore the mechanism of Huangqi Jiedu Decoction (HQJD) in the treatment of breast cancer with the syndrome of Zheng deficiency and toxic incandescence by network pharmacology and molecular docking technology.Methods:The main active ingredients and targets of HQJD were screened through the traditional Chinese medicine (TCM) systematic pharmacology database and analysis platform. The relevant targets of breast cancer with the syndrome of Zheng-deficiency, toxic-incandescence were obtained using OMIM, GeneGards and Drugbank databases, and the relevant targets of HQJD for the treatment of breast cancer with the syndrome of Zheng-deficiency and toxic incandescence were obtained by intersection; The Cytoscape 3.9.1 software was used to build the protein protein interaction (PPI) network and the " drug active component target disease" network on the basis of String 11.0 database, and the core active components and core targets of HQJD in treating breast cancer with the syndrome of Zheng-deficiency and toxic-incandescence were inferred according to the topological parameters. gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on core targets using R language; and molecular docking verification on the main active ingredients and core targets were conducted.Results:230 effective targets of active ingredients of HQJD were screened, and 15 467 active ingredients of breast cancer with syndrome of Zheng-deficiency/toxic-incandescence were obtained; 217 intersection targets; GO function enrichment analysis showed that the treatment of HQJD for breast cancer with the syndrome of Zheng-deficiency and toxic-incandescence mainly involved oxidative stress and cytochemical stress; The enrichment analysis of KEGG pathway showed that HQJD treatment of breast cancer with the syndrome of Zheng-deficiency and toxic-incandescence was mainly related to phosphatidylinositol 3-protein kinase B (PI3K-Akt), interleukin-17 (IL-17) and other signal pathways. The molecular docking results showed that the main active ingredients such as β-sitosterol, stigmasterol, luteolin had good binding ability with core targets.Conclusions:HQJD has the characteristics of multi-component, multi target and multi pathway in the treatment of breast cancer with syndrome of Zheng-deficiency and toxic-incandescence, and its main mechanism may be related to PI3K-Akt, IL-17, P53 and other signal pathways.

[摘 要] 目的：为解决野生型B细胞成熟抗原（BCMA）被γ分泌酶切割导致表达不稳定的问题，构建抵抗γ分泌酶切割的BCMA突变体并构建靶细胞，用于评价BCMA CAR-T细胞的杀伤功能。方法：将野生型BCMA的穿膜域替换为人CD8α穿膜域，构建抵抗γ分泌酶切割的BCMA突变体（BCMA-CD8α TM），构建过表达该突变体的U266（U266BCMA Mut）、K562（K562BCMA Mut）、SKOV3（SKOV3BCMA Mut）和CHO（CHOBCMA Mut）细胞；构建装载NFAT-EGFP报告基因的BCMA CAR Jurkat细胞（BCMA-CAR-Jurkat-Reporter）与U266BCMA Mut细胞共培养，采用FCM检测该细胞中EGFP表达水平以指示NFAT激活水平，荧光素酶法检测BCMA CAR-T细胞对Luciferase标记的K562BCMA Mut细胞的杀伤作用，实时无标记动态细胞分析技术（RTCA）检测BCMA CAR-T细胞对SKOV3BCMA Mut和CHOBCMA Mut细胞的杀伤作用。结果：应用γ分泌酶抑制剂LY411575抑制γ分泌酶活性，显著增强野生型U266细胞表面BCMA表达水平，平均荧光强度上调10倍以上；但撤除抑制剂后BCMA表达水平逐渐降低（P<0.01）；BCMA-CD8α TM突变体可抵抗γ分泌酶的切割作用，在U266细胞表面稳定表达（P>0.05）；U266细胞及过表达BCMA-CD8α TM的U266细胞与BCMA-CAR-Jurkat-Reporter细胞共培养后都可激活Reporter系统、增强EGFP表达，但该效应在BCMA-CD8α TM过表达的U266细胞中更显著（P<0.01）；BCMA-CD8α TM在BCMA表达阴性的K562、SKOV3和CHO 3种靶细胞中成功过表达，且在LY411575处理下该突变体的表达水平仅有小幅度升高；荧光素酶法检测结果显示，不同效靶比下，BCMA CAR-T细胞均可特异、高效杀伤过表达BCMA-CD8α TM的K562细胞；RTCA结果显示，不同效靶比下，BCMA CAR-T细胞均可有效识别、杀伤过表达BCMA-CD8α TM的SKOV3和CHO细胞，但同等效靶比下的Mock-T细胞无此效应。结论：本实验构建的BCMA-CD8α TM突变体能够抵抗γ分泌酶的切割，在多种靶细胞表面稳定表达，为评价BCMA CAR-T细胞体外杀伤的有效性和特异性提供多种检测手段。

BACKGROUND:Human placental mesenchymal stem cells have been shown to be effective in inhibiting the development of pulmonary fibrosis,but the underlying mechanisms remain unclear. OBJECTIVE:To investigate the therapeutic effect and related mechanism of human placental mesenchymal stem cells on silica-induced pulmonary fibrosis in human embryonic lung fibroblasts(MRC-5). METHODS:CCK-8 assay was used to detect the effects of different mass concentrations of silica on the proliferation of MRC-5 at different time points.Immunofluorescence staining was used to screen out the best stimulating mass concentration and time of silica for subsequent experiments.MRC-5 cells were divided into blank group,silica group,and silica + human placental mesenchymal stem cell group.In the blank group,cells were not treated.In the silica group,MRC-5 cells were stimulated with 100 μg/mL silica for 48 hours.In the silica + human placental mesenchymal stem cell group,MRC-5 cells were stimulated with 100 μg/mL silica for 48 hours and then co-cultured with human placental mesenchymal stem cells for 24 hours.Immunofluorescence staining was used to detect the expression of α-smooth muscle actin and collagen type I in cells of each group.Western blot assay was used to detect the expressions of pulmonary fibrosis-related proteins and TGF-β1/Smad 3 signaling pathway-related proteins in cells of each group. RESULTS AND CONCLUSION:(1)CCK-8 assay results suggested that 100 μg/mL silica was the best mass concentration and time to stimulate MRC-5 cells for 48 hours.(2)Immunofluorescence staining results showed that the expression of α-smooth muscle actin and collagen type I in the silica + human placental mesenchymal stem cell group was significantly lower than that in the silica group.(3)Western blot assay results showed that compared with the silica group,the protein expression levels of α-smooth muscle actin,collagen type I,N-cadherin,fibronectin,transforming growth factor-β1,p-Smad3,and Smad3 in the silica + human placental mesenchymal stem cell group were decreased,and the expression of E-cadherin was increased.The difference was statistically significant(P<0.05).(4)The results showed that human placental mesenchymal stem cells had a significant therapeutic effect on silica-induced pulmonary fibrosis.Human placental mesenchymal stem cells can inhibit the development of pulmonary fibrosis by regulating transforming growth factor-β1/Smad3 signaling pathway.

AIM To explore the effects of Zishui Qinggan Decoction on the mouse model of depression induced by chronic restraint stress(CRS)via ERK/GSK3β/CREB/BDNF signaling pathway.METHODS Except for those of the blank group,the mice of other groups were induced into depression models by CRS,and divided into the model group,the fluoxetine hydrochloride group(10 mg/kg)and the low,medium and high dose Zishui Qinggan Decoction groups(8.835,17.670 and 35.340 g/kg)for the corresponding drug intervention and simultanous CRS treatment.The mice had their sugar water preference experiment and behavior experiment on the 7th and 14th day after administration;the observation of the hippocampal morphological changes by HE staining,the detection of the superoxide dismutase(SOD)activity and malondialdehyde(MDA)level in serum by kits,the detection of levels of serum 5-hydroxytryptamine(5-HT),tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)by ELISA,the detection of the hippocampal mRNA expressions of BDNF,TNF-α and IL-1β by RT-qPCR method,and the detection of the hippocampal protein expressions of ERK1/2,p-ERK1/2,GSK3β,p-GSK3β,CREB and BDNF by Western blot method 14 days after administration.RESULTS Compared with the model group,after 14 days of administration,both fluoxetine hydrochloride group and medium-dose Zishui Qinggan Decoction group displayed increased preference rate of sugar water(P<0.01),shortened immobility time of tail suspension and forced swimming(P<0.01),improved hippocampal damage of nerve cells,decreased levels of serum MDA,TNF-α and IL-1β(P<0.05,P<0.01),increased SOD activity and 5-HT level(P<0.05,P<0.01),decreased hippocampal mRNA expressions of TNF-α and IL-1β(P<0.01),and decreased expressions of BDNF mRNA and p-ERK1/2,p-GSK3β,CREB and BDNF proteins(P<0.05,P<0.01).CONCLUSION Zishui Qinggan Decoction can improve the depression-like behaviors in mice exposed to CRS,and its mechanism may be related to the regulation of hippocampal ERK/GSK3β/CREB/BDNF signaling pathway.