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.

The 2-(2-phenylethyl)chromones were separated from agarwood of Aquilaria agallocha Roxb. and their anti-KRAS mutant non-small cell lung cancer (NSCLC) activities were evaluated. 2-(2-Phenyethyl)chromones in agarwood were separated and purified by silica gel, RP-18 reverse phase silica gel, MCI gel CH20P, Diol, and semi preparative HPLC chromatography techniques, while the structures of the compounds were identified by extensive spectroscopic analysis, such as 1D and 2D NMR and ESI-MS. The cell counting kit 8 (CCK-8) assay was used to screen the anti-tumor activity of the isolated monomeric compounds on three KRAS-mutant NSCLC cells. The cell proliferation, cloning formation, adhesion ability, and cell cycle arrest activity of compound 8 were analyzed. Molecular docking and Western blot experiments were used to study the mechanism of compound 8. The in vivo anti-tumor activity of the compound 8 was evaluated by zebrafish cell derived xenograft (CDX) model. Nineteen known 2-(2-phenylethyl)chromones were isolated from the ethyl acetate extract of agarwood. On A549 (KRAS G12S) cells, compounds 8, 10, and 19 showed good inhibitory activity, on H23 (KRAS G12C) cells, compounds 7, 8, and 19 showed good inhibitory activity, and on H358 (KRAS G12C) cells, compounds 8, 10, and 16 showed good inhibitory activity. Compound 8 had the best inhibitory activity in all three cell lines. It effectively inhibited cell proliferation, clone formation, adhesion ability, and arrested the H23 cell cycle at G2/M phase. Compound 8 could also inhibit the expression of c-Met and its downstream signaling pathways, effectively inhibiting tumor growth in zebrafish CDX model. In conclusion, among the nineteen known 2-(2-phenylethyl)chromones, compound 8 had the best activity and significantly inhibited the proliferation of KRAS-mutant NSCLC cells by arresting the cells in the G2/M phase.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Glaucoma is a group of optic neuropathies characterized by the progressive loss of retinal ganglion cells and their axons, and has become a leading cause of irreversible blindness worldwide.However, the pathophysiological mechanisms of glaucoma remain poorly understood.Consequently, suitable animal models of glaucoma are crucial for elucidating the disease's pathogenesis and improving therapeutic strategies.In recent years, rodents have increasingly become the preferred choice for glaucoma modeling due to their numerous advantages.With the exception of transgenic mice, which can spontaneously induce glaucoma, experimental glaucoma models are mainly divided into intraocular pressure-dependent and non-intraocular pressure-dependent models.The intraocular pressure-dependent glaucoma model induces intraocular pressure elevation by obstructing aqueous humor outflow in various ways.The non-intraocular pressure-dependent glaucoma model attempts to study the pathogenesis associated with normal intraocular pressure glaucoma.This article comprehensively reviews the damage mechanisms, operation methods, advantages, and limitations of various rodent models of glaucoma.

Objective To investigate the clinical characteristics and prognosis of pneumococcal meningitis(PM),and drug sensitivity of Streptococcus pneumoniae(SP)isolates in Chinese children.Methods A retrospective analysis was conducted on clinical information,laboratory data,and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.Results Among the 160 children with PM,there were 103 males and 57 females.The age ranged from 15 days to 15 years,with 109 cases(68.1% )aged 3 months to under 3 years.SP strains were isolated from 95 cases(59.4% )in cerebrospinal fluid cultures and from 57 cases(35.6% )in blood cultures.The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87)and 27% (21/78),respectively.Fifty-five cases(34.4% )had one or more risk factors for purulent meningitis,113 cases(70.6% )had one or more extra-cranial infectious foci,and 18 cases(11.3% )had underlying diseases.The most common clinical symptoms were fever(147 cases,91.9% ),followed by lethargy(98 cases,61.3% )and vomiting(61 cases,38.1% ).Sixty-nine cases(43.1% )experienced intracranial complications during hospitalization,with subdural effusion and/or empyema being the most common complication[43 cases(26.9% )],followed by hydrocephalus in 24 cases(15.0% ),brain abscess in 23 cases(14.4% ),and cerebral hemorrhage in 8 cases(5.0% ).Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old,with rates of 91% (39/43)and 83% (20/24),respectively.SP strains exhibited complete sensitivity to vancomycin(100% ,75/75),linezolid(100% ,56/56),and meropenem(100% ,6/6).High sensitivity rates were also observed for levofloxacin(81% ,22/27),moxifloxacin(82% ,14/17),rifampicin(96% ,25/26),and chloramphenicol(91% ,21/23).However,low sensitivity rates were found for penicillin(16% ,11/68)and clindamycin(6% ,1/17),and SP strains were completely resistant to erythromycin(100% ,31/31).The rates of discharge with cure and improvement were 22.5% (36/160)and 66.2% (106/160),respectively,while 18 cases(11.3% )had adverse outcomes.Conclusions Pediatric PM is more common in children aged 3 months to under 3 years.Intracranial complications are more frequently observed in children under 1 year old.Fever is the most common clinical manifestation of PM,and subdural effusion/emphysema and hydrocephalus are the most frequent complications.Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates.Adverse outcomes can be noted in more than 10% of PM cases.SP strains are high sensitivity to vancomycin,linezolid,meropenem,levofloxacin,moxifloxacin,rifampicin,and chloramphenicol.[Chinese Journal of Contemporary Pediatrics,2024,26(2):131-138]

Attenuated Salmonella typhimurium VNP20009 is a widely used natural oncolytic bacterium, which has great application potential given its unique characteristics, including clinical safety, tumor targeting specificity, and explicit genome sequence. Here, we show that tumor progression can be effectively reduced by intraperitoneal administration with VNP20009 in a mouse model of melanoma (all animal experiments were conducted in accordance with the Animal Ethics Committee of China Pharmaceutical University); co-culture experiment in vitro demonstrated that VNP20009 can induce the polarization of macrophage M1, accompanied by expression of inflammation-related factors; flow cytometry analysis showed that VNP20009 induced the increase of immune cell infiltration in tumor. Further analysis showed that T cells infiltration in tumor-draining lymph node (TDLN) increased, and VNP20009 induced the activation of CD4⁺ T cells and CD8⁺ T cells in tumor. Our results demonstrate that VNP20009 treatment significantly inhibited melanoma tumors by remodeling tumor-associated macrophages to an M1-like phenotype, as well as recruiting and activating cytotoxic T cells, combined with its own antigenic activity to exert anti-tumor immunity.

AIM: To explore the characteristics of astigmatism in preschool children before, during and after the COVID-19 epidemic, so as to provide a reference for further prevention and control of children's vision.METHODS: In the consecutive four years from January 2018 to December 2021, a retrospective analysis of vision data was conducted on 2 273 preschool children(4 546 eyes)younger than 4 years old who participated in children's vision screening test in Baiyun district, Guangzhou. They were divided into 1-year old group(ages<1-year old, 420 cases), 2-year old group(1-year ≤ ages <2-year, 543 cases), 3-year old group(2-year ≤ages <3-year, 614 cases), and 4-year old group(3-year ≤ ages<4-year, 696 cases)according to ages. The analysis included astigmatic degrees of children's eyes as well as their conditions of astigmatism.RESULTS: In 2018, the astigmatic degrees of the both eyes of 1-year-old group were higher than those of other groups(P<0.05). The binocular astigmatic degrees of the preschool children in four groups were obviously higher in 2020 than 2019(P<0.05), while they were significantly decreased in 2021 when compared with 2020(P<0.05). From 2019 to 2020, the increase of astigmatic degrees of the right eye is more considerable than the left eye of preschool children in those four groups(P<0.001). Furthermore, the morbidity of astigmatism basically echoes with the changing tendency of astigmatic degrees from 2018 to 2021.CONCLUSIONS: Preschool children in Baiyun district, Guangzhou, have the highest degree of astigmatism and the fastest progression rate within 1 year old. Before COVID-19 epidemic, the changes in astigmatism and prevalence were relatively stable; during COVID-19 epidemic, the astigmatism and prevalence increased significantly and the astigmatic degrees of right eye increased more than that of the left eye; after the normalization of epidemic prevention and control, the astigmatism and prevalence decreased significantly.

Objective: To observe the effects of exosomes derived from human umbilical cord mesenchymal stem cells on the proliferation and invasion of pancreatic cancer cells, and to analyze the contents of exosomes and explore the mechanisms affecting pancreatic cancer cells. Methods: Exosomes extracted from human umbilical cord mesenchymal stem cells were added to pancreatic cancer cells BxPC3, Panc-1 and mouse models of pancreatic cancer, respectively. The proliferative activity and invasion abilities of BxPC3 and Panc-1 cells were measured by cell counting kit-8 (CCK-8) and Transwell assays. The expressions of miRNAs in exosomes were detected by high-throughput sequencing. GO and KEGG were used to analyze the related functions and the main metabolic pathways of target genes with high expressions of miRNAs. Results: The results of CCK-8 cell proliferation assay showed that the absorbance of BxPC3 and Panc-1 cells in the hucMSCs-exo group was significantly higher than that in the control group [(4.68±0.09) vs. (3.68±0.01), P<0.05; (5.20±0.20) vs. (3.45±0.17), P<0.05]. Transwell test results showed that the number of invasion cells of BxPC3 and Panc-1 in hucMSCs-exo group was significantly higher than that in the control group (129.40±6.02) vs. (89.40±4.39), P<0.05; (134.40±7.02) vs. (97.00±6.08), P<0.05. In vivo experimental results showed that the tumor volume and weight in the exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) group were significantly greater than that in the control group [(884.57±59.70) mm(3) vs. (695.09±57.81) mm(3), P<0.05; (0.94±0.21) g vs. (0.60±0.13) g, P<0.05]. High-throughput sequencing results showed that miR-148a-3p, miR-100-5p, miR-143-3p, miR-21-5p and miR-92a-3p were highly expressed. GO and KEGG analysis showed that the target genes of these miRNAs were mainly involved in the regulation of glucosaldehylation, and the main metabolic pathways were ascorbic acid and aldehyde acid metabolism, which were closely related to the development of pancreatic cancer. Conclusion: Exosomes derived from human umbilical cord mesenchymal stem cells can promote the growth of pancreatic cancer cells and the mechanism is related to miRNAs that are highly expressed in exosomes.
Mice ; Animals ; Humans ; MicroRNAs/metabolism* ; Exosomes/genetics* ; Sincalide/metabolism* ; Pancreatic Neoplasms/metabolism* ; Carcinoma, Pancreatic Ductal/genetics* ; Mesenchymal Stem Cells/metabolism* ; Umbilical Cord

Objective:Immune checkpoint inhibitors have a high remission rate in the preoperative application of resectable and potentially resectable non-small cell lung cancer when combined with chemotherapy. For the unresectable stage Ⅲ non-small cell lung cancer, whether the transformation can be achieved through this regimen to provide opportunities for surgical resection is controversial. In this study, we evaluated the pattern of transformation therapy by reviewing the efficacy and safety of preoperative therapy and surgery of this group.Methods:A review of 23 patients undergoing surgical resection after transformation therapy by preoperative immunotherapy combined chemotherapy between November 2019 and November 2021 was performed. All patients must clarify the pathological diagnosis of non-small cell lung cancer by biopsy. After the multi-disciplinary treatment team and preoperative imaging assessment, the diagnosis should be consistent with unresectable stage III as described in the Expert Consensus on Multidisciplinary Management of Stage Ⅲ Non-Small Cell Lung Cancer, 2019 Edition. After 2 to 4 cycles of preoperative anti-PD-1 monoclonal antibody combined with chemotherapy, the surgical team assessed the chance of resection and performed surgery. Important indicators such as surgical resection rate, R0 resection rate, MPR, pCR, incidence of grade 3-5 adverse reactions and various other perioperative data were counted.Results:In the whole group, initial imaging evaluation was 10 of stage cⅢA and 13 of stage cⅢB.15 cases had multiple stations N2 lymph nodes metastasis, 9 had enlarged fused N2 lymph nodes metastasis, 6 had large vessel invasion(T4), and 1 had contralateral mediastinal lymph node metastasis(N3). After preoperative neoadjuvant therapy, 17 cases achieved PR, 3 achieved SD and 3 achieved PD. The surgical resection rate of the whole group was 91.3%(21/23, 1 lobectomy combined with superior vena cava reconstruction, 2 sleeve lobectomy, 5 pneumonectomy, 12 lobectomy/combined lobectomy, 1 wedge resection and 2 unresectable cases), R0 resection rate was 95.2%(20/21). MPR was achieved in 13 cases, 8 of them reached pCR. There were no perioperative deaths, median surgical time was 260(190-460) min, median bleeding volume was 100(50-750) ml, median drainage time was 5(3-9) days, and median hospitalization was 7(5-11) days. Two cases got immunotherapy-related grade 3 adverse reactions, one was interstitial pneumonia and the other was immune-related injury involving the eye, oral and genital mucosa. Two cases got surgical complications and one was persistent lung leakage, which stopped after 46 days of conservative treatment; The other was pleural effusion, which was relieved after drainage.Conclusion:For the unresectable stage Ⅲ NSCLC, immunotherapy combined chemotherapy is an effective preoperative downstage method. It can convert 91.3% cases to resectable ones while achieving a good degree of pathological remission. Its side reactions are generally controllable and safety.

Objective To explore the efficacy and safety of dabigatran etexilate in the treatment of elderly patients with non-valvular atrial fibrillation (NVAF), so as to provide reference for clinical treatment and rational drug use. Methods Eighty elderly patients with NVAF in The Seventh People's Hospital of Shanghai from December 2020 to June 2021, aged 65 to 80 years, were enrolled in a self-controlled study. Dabigatran etexilate 110 mg was given orally, twice a day (one in the morning and one in the evening) for 6 months. During the follow-up visit, the coagulation function indexes including APTT, TT, FIB and D-D were observed in patients taking medicine for 1 month and 6 months. Liver function indexes including ALT, AST and TBIL, renal function indicators including UREA and eGFR, and blood routine indexes including HGB and ESR, also were observed in patients taking medicine for 1 month and 6 months. Results Patients were compared at 1 month and 6 months after treatment with dabigatran and before: the difference of coagulation function indexes as APTT and TT was statistically significant (P<0.05);There was no significant difference in liver function index, renal function index and blood routine index (P>0.05); A total of 25 adverse events occurred, and the incidence rate of adverse reactions was 31.25%, there was no adverse events such as serious hemorrhage，life threatening and organ failure hemorrhage occurred．Conclusion Dabigatran has good efficacy and safety in the treatment of the elderly NVAF.