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.

In order to explore the possible role and molecular mechanism of the combined action of leech and bear bile in liver and gallbladder diseases, this study first used network pharmacology methods to screen the components and targets of leech and bear bile, as well as the related target genes of liver and gallbladder diseases. The selected key genes were subjected to interaction network and GO/KEGG enrichment analysis. Then, using sodium oleate induced HepG2 cell lipid deposition model and DL-ethionine induced mouse fatty liver model, the activity of leech and bear bile alone and in combination in reducing liver fat was evaluated in vitro and in vivo, and the expression of key pathway related proteins suggested by network pharmacology was detected by Western blot. The results of network pharmacology analysis showed that the active ingredients of leech and bear bile have 295 intersecting targets with liver and gallbladder related diseases, involving more than 200 signaling pathways, including the PI3K/Akt signaling pathway and phospholipase D signaling pathway closely related to glucose and lipid metabolism. The results of in vitro validation experiments showed that both leech and bear bile, alone and in combination, can significantly inhibit the lipid deposition induced by sodium oleate in human liver cells, reduce the triacylglycerol level in cell culture supernatant, and inhibit the lipid content in liver cells. The observation results of Nile red staining confocal microscopy showed that the combination of leech and bear bile had better activity in reducing lipid deposition in liver cells compared to using them alone. In a mouse fatty liver model, the combination of leech and bear bile can better reduce elevated organ indices, blood lipids, and liver lipid levels, as well as lower the levels of serum liver injury biomarkers. The animals used in this experiment and related disposal meet the requirements of animal welfare. Before the experiment, it was reviewed and approved by IACUC, Institute of Materia Medica, Chinese Academy of Medical Sciences. The Western blot experiment results showed that the combination of leech and bear bile can significantly upregulate the expression levels of p-PI3K and p-Akt proteins, and increase the p-PI3K/PI3K and p-Akt/Akt ratios, which is consistent with the predicted results of network pharmacology. The combination of leech and bear bile has great potential for treating fatty liver disease, and activating the PI3K/Akt pathway may be one of the important mechanisms for reducing lipid deposition in liver cells.

The chemical constituents in dried roots of Atractylodes macrocephala were investigated in this study. Through utilizing normal-phase silica gel and ODS column chromatography, TLC, and semi-preparative HPLC, 4 new sesquiterpenoids were purified from the ethyl acetate extract of A. macrocephala. By various spectroscopic techniques, such as 1D and 2D NMR, HR-ESI-MS, IR, UV, and CD, their structures were identified as atractylmacron A (1), 9β-hydroxyasterolide (2), atractylenolide H (3), atractylenolide J (4). Compound 1 possesses a rare 6/7 bicyclic skeleton.

Objective:To evaluate the efficacy of acute T-cell lymphoblastic leukemia(T-ALL)in children and explore the prognostic risk factors.Methods:The clinical data of 127 newly diagnosed children with T-ALL admitted to five hospitals in Fujian province from April 2011 to December 2020 were retrospectively analyzed,and compared with children with newly diagnosed acute precursor B-cell lymphoblastic leukemia(B-ALL)in the same period.Kaplan-Meier analysis was used to evaluate the overall survival(OS)and event-free survival(EFS),and COX proportional hazard regression model was used to evaluate the prognostic factors.Among 116 children with T-ALL who received standard treatment,78 cases received the Chinese Childhood Leukemia Collaborative Group(CCLG)-ALL 2008 protocol(CCLG-ALL 2008 group),and 38 cases received the China Childhood Cancer Collaborative Group(CCCG)-ALL 2015 protocol(CCCG-ALL 2015 group).The efficacy and serious adverse event(SAE)incidence of the two groups were compared.Results:Proportion of male,age ≥ 10 years old,white blood cell count(WBC)≥ 50 × 109/L,central nervous system leukemia,minimal residual disease(MRD)≥ 1％during induction therapy,and MRD ≥ 0.01％at the end of induction in T-ALL children were significantly higher than those in B-ALL children(P＜0.05).The expected 10-year EFS and OS of T-ALL were 59.7％and 66.0％,respectively,which were significantly lower than those of B-ALL(P＜0.001).COX analysis showed that WBC ≥ 100 x 109/L at initial diagnosis and failure to achieve complete remission(CR)after induction were independent risk factors for poor prognosis.Compared with CCLG-ALL 2008 group,CCCG-ALL 2015 group had lower incidence of infection-related SAE(15.8％vs 34.6％,P=0.042),but higher EFS and OS(73.9％vs 57.2％,PEFS=0.090;86.5％vs 62.3％,PoS=0.023).Conclusions:The prognosis of children with T-ALL is worse than children with B-ALL.WBC ≥ 100 × 109/L at initial diagnosis and non-CR after induction(especially mediastinal mass has not disappeared)are the risk factors for poor prognosis.CCCG-ALL 2015 regimen may reduce infection-related SAE and improve efficacy.

Objective:To analyze the related factors of treatment failure in children with acute lymphoblastic leukemia (ALL)in real-world.Methods:The clinical data of 1414 newly diagnosed children with ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed.Treatment failure was defined as relapse,non-relapse death,and secondary tumor.Results:Following-up for median time 49.7 (0.1-136. 9)months,there were 269 cases (19.0％)treatment failure,including 140 cases (52.0％)relapse,and 129 cases (48.0％)non-relapse death.Cox univariate and multivariate analysis showed that white WBC≥50 ×109/L at newly diagnosis,acute T-cell lymphoblastic leukemia (T-ALL),BCR-ABL1,KMT2A-rearrangement and poor early treatment response were independent risk factor for treatment failure (all HR>1.000,P<0.05).The 5-year OS of 140 relapsed ALL patients was only 23.8％,with a significantly worse prognosis for very early relapse (relapse time within 18 months of diagnosis).Among 129 patients died from non-relapse death,71 cases (26.4％)were died from treatment-related complications,56 cases (20.8％)died from treatment abandonment,and 2 cases (0.7％)died from disease progression.Among them,treatment-related death were significantly correlated with chemotherapy intensity,while treatment abandonment were mainly related to economic factors.Conclusion:The treatment failure of children with ALL in our province is still relatively high,with relapse being the main cause of treatment failure,while treatment related death and treatment abandonment caused by economic factors are the main causes of non-relapse related death.

Objective:To prepare an affinity-based radionuclide therapeutic drug targeting human epidermal growth factor receptor 2 (HER2), named 177Lu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-HER2-BCH, and preliminarily evaluate its biodistribution, therapeutic efficacy, and safety in HER2-positive tumor models, in order to explore its feasibility as a radiopharmaceutical for treatment of HER2-positive tumor. Methods:177Lu labeling was accomplished by using a hydrochloric acid-sodium acetate buffer system. The radiochemical purity and in vitro stability of the labeled products were analyzed by radio high performance liquid chromatography. Biodistribution, 177Lu-DOTA-HER2-BCH radionuclide targeting therapy, and trastuzumab therapy were performed in the HER2-positive NCI-N87 tumor-bearing mice. Repeated measures analysis of variance and Bonferroni method were utilized to analyze data. Results:177Lu-DOTA-HER2-BCH was obtained, with the radiolabeling yield >80%, radiochemical purity >98%, and good in vitro stability. Biodistribution data showed that 177Lu-DOTA-HER2-BCH was well targeted, with high tumor uptake and high retention. The tumor uptake values at 4, 24, 72 and 96 h post-injection were (11.93±0.46), (8.65±0.40), (5.89±0.69) and (3.26±0.36) percentage activity of injection dose per gram of tissue (%ID/g), respectively. In the treatment experiment, 177Lu-DOTA-HER2-BCH significantly inhibited tumor growth. On the 3rd day, the tumor volume of mice treated with 177Lu-DOTA-HER2-BCH was significantly smaller than that of the control group (mean difference 146.97 mm 3;F=4.02, P=0.016 (Bonferroni correction method), and then differences of tumor volume between the 2 groups increased with time. The differences of tumor volume between 177Lu-DOTA-HER2-BCH and trastuzumab treatment groups were not statistically significant throughout the treatment process ( F values: 0.05-61.21, all P>0.017(Bonferroni correction method)). At the end of treatment, no histological abnormality was seen in all organs of the mice. Conclusion:177Lu-DOTA-HER2-BCH radionuclide therapy demonstrates good tumor growth inhibition in HER2-positive tumor-bearing mice, which is expected to be an alternative treatment for HER2-positive tumors.

AIM To explore the clinical effects of Shuilu Erxian Pills combined with Modified Didang Decoction on patients with early and middle stage diabetic nephropathy.METHODS Eighty-three patients were randomly assigned into control group(42 cases)for 12-week administration of Irbesartan Tablets,and observation group(41 cases)for 12-week administration of Shuilu Erxian Pills,Modified Didang Decoction and Irbesartan Tablets.The changes in clinical effects,TCM syndrome scores,blood glucose indices(FBG,HbA1c),blood lipid indices(TC,TG),renal function indices(BUN,Scr,24 h UTP,eGFR),inflammatory factors(IL-1β,hs-CRP,IL-6,TNF-α,IL-18,TGF-β1),immune function indices(lymphocyte,neutrophil,CD8+,CD3+,CD4+,CD4+/CD8+)and incidence of adverse reactions were detected.RESULTS The observation group demonstrated higher total effective rate than the control group(P＜0.05).After the treatment,the observation group displayed decreased TCM syndrome scores,blood glucose indices,blood lipid indices,BUN,Scr,24 h UTP,inflammatory factors,CD8+(P＜0.05),reduced lymphocyte,neutrophil(P＜0.05),and increased eGFR,CD3+,CD4+,CD4+/CD8+(P＜0.05),which were more obvious than those in the control group(except for HbA1c,TG,SCr,24 h UTP,lymphocyte,neutrophil)(P＜0.05).No significant difference in incidence of adverse reactions was found between the two groups(P＞0.05).CONCLUSION For the patients with early and middle stage diabetic nephropathy,Shuilu Erxian Pills combined with Modified Didang Decoction can safely and effectively improve clinical symptoms,whose mechanism may contribute to the reduction of inflammatory levels and improvement of immune functions.

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]

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective To analyze the clinical and serological typing characteristics of invasive Haemophilus influ-enzae(Hin)infection in children.Methods Clinical data of 34 children with invasive Hin infection admitted to Children's Hospital of Shanxi from 2015 to 2021 were analyzed retrospectively.According to clinical diagnosis,they were divided into meningitis infection group and non-meningitis infection group.General data,symptoms,signs,laboratory serological indicators,and Hin serum typing characteristics of children,as well as differences in inflammatory factor level between the two groups were analyzed.Results Among the 34 patients,22 were males and 12 were females,with a male to female ratio of 1.83∶1.Children aged ≤36 months accounted for 82.35％.The levels of procalcitonin(PCT)(23.71[4.10,77.80])ng/mL and C-reactive protein(CRP)(200.00[164.55,200.00])mg/L in children in the meningitis infection group were higher than those in the non-meningitis group(1.08[0.49,6.00]ng/mL,69.46[48.09,125.63]mg/L,respectively),with statistically significant differences(both P＜0.05).The platelet(PLT)count in the non-meningitis group([312.56±186.81]× 109/L)was higher than that in the meningitis group([183.28±165.67]× 109/L),with statistically significant difference(P＜0.05).There was no statistically significant difference in white blood cell(WBC)count and neutrophil(NEUT)percentage between two groups(both P＞0.05).Among the isolated Hin strains,27,2,and 2 strains were type b(Hib),e and f,respectively;3 strains were not typed;serotype a,c and d strains were not found.There was no statistically significant difference in the distribution of typeable Hin strains between the two groups(x2=0.25,P＞0.05).There was no statistically significant difference in the constituent rate of typeable Hin strains between male and fe-male children(67.74％vs 32.26％,x2=1.42,P＞0.05).Conclusion The majority of invasive Hin infection cases are children under 3 years old,and the predominant strain is type b.CRP and PCT levels of infected children in-creased significantly,while PLT is significantly lower than that of non-infected children,which has certain clinical diagnostic value and can provide effective support for early classified diagnosis and anti-infection treatment of inva-sive infectious diseases combined with other clinical testing items.