Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

Objective To noninvasively predict isocitrate dehydrogenase(IDH)status of glioma via combining imaging and clini-cal features before surgery,so as to provide basis for individualized clinical treatment decision.Methods A total of 47 patients with glioma confirmed by pathological and molecular genetic tests were included,including 20 with IDH mutant type and 27 with IDH wild type.After diffusion tensor imaging(DTI)scanning,fractional anisotropy(FA)and mean diffusivity(MD)values of tumor paren-chyma were calculated.Combining DTI parameters with MRI morphological features of tumor,blood neutrophil/lymphocyte ratio(NLR)and patient's age,binary logistic regression model was established to effectively predict IDH status of glioma patients before surgery.Results There were significant differences in FAmean/FANAWM,MDmin,NLR,tumor location and age between IDH mutant type and IDH wild type groups(P<0.05).The binary logistic regression model concluding,FAmean/FANAWM,MDmin,cystic degeneration,NLR and age,predicted IDH status of glioma with area under the curve(AUC)of 0.961 and 95%confidence interval(CI)of 0.914-1.00.Conclusion The regression model established via combining DTI,MRI morphological features and blood NLR has great performance in classifying IDH status of glioma,and can help predict IDH status noninvasively before surgery,so as to assist clinical individualized treatment.

The process of establishing and improving the Employee Health Insurance Outpatient Co-payment Protection Mecha-nism is one of the major livelihood projects to deepen the reform of China's medical insurance system.The implementation of the mu-tual-aid mechanism for covering outpatient bills in each coordinating region is accompanied by the risks of squeezing outpatient medi-cal resources,the prevalence of fraud and deception,the increase of the government s economic burden and the lack of public ac-ceptance.In this regard,suggestions are made to improve the policy:open source and cut costs to make up for the shortage of funds,linkage of three medical institutions to build a medical security pattem,coordinated supervision to maintain the stability of medical insurance funds,and optimized policies to promote the reform of medical insurance payment methods.

Background Aluminum and fluoride are neurotoxic, and aluminum exposure alone is closely related to the overall cognitive function of operational workers. It is unclear about the effect of aluminum and fluoride interactions on cognitive function. Objective To evaluate a potential interaction effect of blood aluminum and urinary fluoride on the overall cognitive function of workers working in an aluminum plant. Methods Using cluster sampling, 230 workers in the electrolysis workshop of an aluminum group company in Shanxi Province were selected, and plasma aluminum concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS) and urinary fluoride by ion-selective electrode. The study participants were divided into a low blood aluminum group and a high blood aluminum group according to the median (M) of blood aluminum concentration, and a low urinary fluoride group and a high urinary fluoride group by a predetermined cutoff point (2.160 mg·L⁻¹). The Montreal Cognitive Assessment-Beijing (MoCA-BJ) was used to assess overall cognitive function of the workers. Logistic regression model was used to analyze the relationship between blood aluminum, urinary fluoride, and mild cognitive impairment (MCI), including multiplicative interaction analysis and correlation analysis; R language was used to fit an additive interaction model of blood aluminum and urinary fluoride on MCI and to calculate synergy index (S), relative excess risk due to interaction (RERI), and attributable proportion due to interaction (API). Results Among the 230 operational workers, the median blood aluminum concentration (P₂₅, P₇₅) was 40.11 (25.16, 58.89) µg·L⁻¹, and there were 104 cases of abnormal urinary fluoride, with an abnormality rate of 45.2%. There was a multiplicative interaction (OR=7.783, 95%CI: 1.377, 43.991) and no additive interaction (RERI=0.030, 95%CI: −0.498, 0.559; API=0.018, 95%CI: −0.279, 0.316; S=1.049, 95%CI: 0.519, 2.118) for the effect between blood aluminum and urinary fluoride on overall cognitive function of the workers. The logistic regression analysis showed that the risk of MCI was 12.105 (95%CI: 2.802, 52.287) times higher in workers with both high blood aluminum and high urinary fluoride than in those with low blood aluminum and low urinary fluoride, after adjusting for selected influencing factors. Conclusion Occupational exposure related high blood aluminum and high urinary fluoride are risk factors for cognitive dysfunction, and the coexistence of both indicators increases the risk of MCI in workers with occupational aluminum exposure, with a multiplicative interaction.

OBJECTIVES: This study aimed to analyze the bacteria in dental caries and establish an optimized dental-ca-ries diagnosis model based on 16S ribosomal RNA (rRNA) data of oral flora. METHODS: We searched the public databa-ses of microbiomes including NCBI, MG-RAST, EMBL-EBI, and QIITA and collected data involved in the relevant research on human oral microbiomes worldwide. The samples in the caries dataset (1 703) were compared with healthy ones (20 540) by using the microbial search engine (MSE) to obtain the microbiome novelty score (MNS) and construct a caries diagnosis model based on this index. Nonparametric multivariate ANOVA was used to analyze and compare the impact of different host factors on the oral flora MNS, and the model was optimized by controlling related factors. Finally, the effect of the model was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: 1) The oral microbiota distribution obviously differed among people with various oral-health statuses, and the species richness and species diversity index decreased. 2) ROC curve was used to evaluate the caries data set, and the area under ROC curve was AUC=0.67. 3) Among the five hosts' factors including caries status, country, age, decayed missing filled tooth (DMFT) indices, and sampling site displayed the strongest effect on MNS of samples (P=0.001). 4) The AUC of the model was 0.87, 0.74, 0.74, and 0.75 in high caries, medium caries, low caries samples in Chinese children, and mixed dental plaque samples after controlling host factors, respectively. CONCLUSIONS The model based on the analysis of 16S rRNA data of oral flora had good diagnostic efficiency.
Humans ; Child ; Bacteria/genetics* ; Dental Caries/microbiology* ; Dental Caries Susceptibility ; Microbiota/genetics* ; RNA, Ribosomal, 16S

OBJECTIVE: To explore the clinical phenotype and genetic variant in a child with Verheij syndrome (VRJS). METHODS: A child who had presented at the Soochow University Affiliated Children's Hospital and Wujiang District Children's Hospital in July 2022 for "elevated scapula since early childhood" was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child had manifested elevated scapulae, torticollis, neck asymmetry, facial dysmorphism, dispersed café-au-lait spots, limited mobility of upper limbs and shoulder joints, and intellectual disability. Sequencing revealed that he has harbored a de novo heterozygous c.405dupT (p.Ile136Tyrfs*4) variant of the PUF60 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic (PVS1+PS2_moderate+PM2_supporting). Combined his clinical features and result of genetic testing, the child was diagnosed with VRJS due to variant of the PUF60 gene. CONCLUSION The clinical manifestations of VRJS include facial dysmorphism, intellectual disability, elevated scapulae, vertebral fusion, other skeletal malformations, without significant abnormalities of the heart, kidney, and eyes, which need to be distinguished from Klippel-Feil syndrome. Above finding has expended the mutation spectrum of the PUF60 gene and provided a reference for delineation of the genotype-phenotype correlation of the VRJS.
Child ; Child, Preschool ; Humans ; Male ; Cafe-au-Lait Spots ; Computational Biology ; Genetic Testing ; Genomics ; Intellectual Disability/genetics* ; Mutation

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with unknown etiology and limited therapeutic options. Activation of fibroblasts is a prominent feature of pulmonary fibrosis. Here we report that lncRNA DACH1 (dachshund homolog 1) is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis. LncDACH1 knockout mice develop spontaneous pulmonary fibrosis, whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation, collagen deposition and differentiation of mouse lung fibroblasts. Similarly, forced expression of LncDACH1 not only prevented bleomycin (BLM)-induced lung fibrosis, but also reversed established lung fibrosis in a BLM model. Mechanistically, LncDACH1 binding to the serine/arginine-rich splicing factor 1 (SRSF1) protein decreases its activity and inhibits the accumulation of Ctnnb1. Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts. Furthermore, loss of LncDACH1 promoted proliferation, differentiation, and extracellular matrix (ECM) deposition in mouse lung fibroblasts, whereas such effects were abolished by silencing of Ctnnb1. In addition, a conserved fragment of LncDACH1 alleviated hyperproliferation, ECM deposition and differentiation of MRC-5 cells driven by TGF-β1. Collectively, LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation, suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.