Protein disulfide isomerase A6 (PDIA6) is closely related to inflammation and endoplasmic reticulum stress. To obtain the glycosyl derivatives of benzophenone polyphenols targeting PDIA6 with strong anti-inflammatory effects, twenty-five target glycosyl derivatives were synthesized by Friedel-Crafts acylation and deacetylation reaction, starting from the substituted benzophenone and α-bromoacetyl saccharide, and their interactions with PDIA6 were quantitatively investigated by bio-layer interferometry (BLI) technique. Their in vitro anti-inflammatory properties were also evaluated. The results showed that target compounds 4b, 10b, 17b, 18b, and 25b not only exhibit high affinity with PDIA6, but also present strong anti-inflammatory abilities. Above results suggest that this class of compounds can affect the signaling pathways related to inflammation by directly acting on PDIA6. In particular, such compounds exhibit the strong inhibitory effects on IL-1β and IL-6 release, suggesting the potential development prospect in the treatment of inflammatory diseases.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

Objective: To examine the associations of childhood obesity, assessed by genetic variations of childhood body mass index (BMI), with the risk of adult ischemic heart disease (IHD) and major coronary event (MCE). Methods: More than 69 000 participants from the China Kadoorie Biobank were genotyped. After excluding those with coronary heart disease, stroke, or cancer at baseline, a total of 64 454 participants were included in this study. Based on genome-wide significant single nucleotide polymorphisms (SNPs), childhood BMI genetic risk score were constructed for every participant and divided into quintiles, with the lowest quintile as the low genetic risk group and the highest quintile as the high genetic risk group. Cox proportional hazards regression models were used to estimate the association between genetic predisposition to childhood obesity and the risk of ischemic heart disease. Results: During a median of 10.7 years of follow-up, 7 073 incident cases of IHD and 1 845 cases of MCE were documented. After adjusting for sex, age, region, and the first ten genetic principal components, the HRs (95%CIs) for IHD and MCE in the high genetic risk group were 1.10 (1.02-1.18) and 1.10 (0.95-1.27), compared with the low genetic risk group. IHD risk increased by 4% (2%-6%) for each one standard deviation increase in genetic risk score (trend P=0.001). After further adjustment for baseline BMI, the differences between genetic risk groups were not statistically significant, but there was still a linear trend between genetic risk score and IHD risk (trend P=0.019). Conclusions: IHD risk increased with genetic predisposition to childhood obesity, suggesting that childhood obesity is an important risk factor for the development of IHD in China. As an easily identifiable feature, changes of childhood BMI should be monitored regularly to realize early intervention of IHD in adults.
Adult ; Body Mass Index ; Child ; China/epidemiology* ; Genetic Predisposition to Disease ; Humans ; Myocardial Ischemia/genetics* ; Pediatric Obesity/genetics* ; Prospective Studies ; Risk Factors

Extracellular matrix (ECM) stiffness is closely related to the physiological and pathological states of breast tissue. The current study was aimed to investigate the effect of silk fibroin/collagen composite hydrogels with adjustable matrix stiffness on the growth and phenotype of normal breast epithelial cells. In this study, the enzymatic reaction of horseradish peroxidase (HRP) with hydrogen peroxide (H₂O₂) was used to change the degree of cross-linking of the silk fibroin solution. The rotational rheometer was used to characterize the composite hydrogel's biomechanical properties. Human normal mammary epithelial cell line MCF-10A were inoculated into composite hydrogels with various stiffness (19.10-4 932.36 Pa) to construct a three dimensional (3D) culture system of mammary epithelial cells. The CCK-8 assay was applied to detect the cell proliferation rate and active states in each group. Hematoxylin-Eosin (HE) staining and whole-mount magenta staining were used for histological evaluation of cell morphology and distribution. The results showed that with the increase of matrix stiffness, MCF-10A cells exhibited inhibited proliferation rate, decreased formation of acinus structures and increased branching structures. Meanwhile, with the increase of matrix stiffness, the polarity of MCF-10A cells was impeded. And the increase of matrix stiffness up-regulated the expression levels of mmp-2, mmp-3, and mmp-9 in MCF-10A cells. Among the genes related to epithelial-mesenchymal transition (EMT), the expression level of the epithelial marker gene E-cadherin was significantly down-regulated, while the interstitial cell marker gene Vimentin was up-regulated, and the expression levels of Snail, Wnt5b and Integrin β1 in the Wnt pathway were up-regulated. These results suggest that the silk fibroin/collagen composite hydrogels with adjustable matrix stiffness regulates the proliferation and the phenotype of MCF-10A cells. The effects of increased matrix stiffness may be closely related to the changes of the polar structures and function of MCF-10A cells, as well as the occurrence of ECM-remodeling and EMT.
Collagen/metabolism* ; Epithelial Cells/metabolism* ; Fibroins/pharmacology* ; Humans ; Hydrogels/metabolism* ; Hydrogen Peroxide ; Phenotype

The ventral part of the anteromedial thalamic nucleus (AMv) is in a position to convey information to the cortico-hippocampal-amygdalar circuit involved in the processing of fear memory. Corticotropin-releasing-factor (CRF) neurons are closely associated with the regulation of stress and fear. However, few studies have focused on the role of thalamic CRF neurons in fear memory. In the present study, using a conditioned fear paradigm in CRF transgenic mice, we found that the c-Fos protein in the AMv CRF neurons was significantly increased after cued fear expression. Chemogenetic activation of AMv CRF neurons enhanced cued fear expression, whereas inhibition had the opposite effect on the cued fear response. Moreover, chemogenetic manipulation of AMv CRF neurons did not affect fear acquisition or contextual fear expression. In addition, anterograde tracing of projections revealed that AMv CRF neurons project to wide areas of the cerebral cortex and the limbic system. These results uncover a critical role of AMv CRF neurons in the regulation of conditioned fear memory.

Caveolin-1 (CAV-1) is related to inflammation, oxidative damage, and immunity. In order to obtain a series of dibenzoylmethane halophenols with strong anti-inflammatory and antioxidant effects targeting CAV-1, twenty-nine target compounds were therefore synthesized by Baker-Ventaraman rearrangement and demethylation reaction, starting from the substituted benzoyl chloride and o-hydroxyacetophenone, and their interactions with CAV-1 were investigated by BLI technique. Their in vitro anti-inflammatory and antioxidant properties were also evaluated. The results showed that compounds A6, A17, A18, and A29 not only specifically bind to CAV-1, but also present strong anti-inflammatory and antioxidant effects. These results suggest that this class of compounds can affect the signaling pathways related to inflammation and oxidative stress by directly acting on CAV-1. In particular, these compounds exhibit the most significantly inhibitory effects on IL-1β and COX-2 release. IL-1β plays a key regulatory role in the development of arthritis. Therefore, it is worth expecting for the application of such compounds in the prevention and treatment of arthritis.

Aortic Valve/surgery* ; Aortic Valve Stenosis/surgery* ; China/epidemiology* ; Heart Valve Prosthesis Implantation ; Humans ; Severity of Illness Index ; Treatment Outcome

This paper discussed the synergistic anti-tumor effect of Shuangdan Capsules combined with 5-fluorouracil(5-FU) on human liver cancer cell line Huh-7 and tumor bearing mice. The effects of Shuangdan Capsules combined with 5-FU on the activity and vascular endothelial growth factor(VEGF) receptor protein expression of Huh-7 cells were investigated, and the effects of drug combination on tube formation of HUVEC cell were also verified. In addition, the mice model of Huh-7 was established to observe the anti-tumor effect of drug combination and the distribution of tumor blood flow in tumor bearing mice by using molecular imaging. HPLC analysis showed that Shuangdan Capsules mainly consisted of danshensusodium, protocatechuic aldehyde, paeoniflorin, rosmarinic acid, alkannic acid, salvianolic acid B, and paeonol. In MTT experiment, the inhibition rate of Shuangdan Capsules(20 mg·L~(-1)) and 5-FU(1 μmol·L~(-1)) on Huh-7 cells was 60%, and the CI value was 0.59, suggesting that these two drugs had synergistic anti-hepatoma cells effect. The expression of VEGF receptor in Huh-7 cells was inhibited by the combination of these two drugs. In addition, the process of HUVEC was slow, and the number, length and area of the lumen branches decreased significantly. In vivo, Shuangdan Capsules combined with 5-FU inhibited the growth and prolongation of survival of Huh-7 cells in subcutaneous transplanted tumor nude mice; serum expression of CD31 and VEGF in nude mice were decreased, while caspase-3 was increased. Meanwhile, the drug combination significantly inhibited the expressions of MMP2 and VEGF in tumor tissues. Ultrasound showed that Shuangdan Capsules combined with 5-FU also inhibited tumor angiogenesis and reduced blood flow of tumor tissue. The results showed that Shuangdan Capsules combined with 5-FU may inhibit tumor angiogenesis by inhibiting VEGF and MMP2 expressions, thereby blocking tumor growth.
Animals ; Capsules ; Carcinoma, Hepatocellular ; Cell Line, Tumor ; Cell Proliferation ; Drugs, Chinese Herbal ; Fluorouracil ; Heterografts ; Liver Neoplasms ; Mice ; Mice, Nude ; Vascular Endothelial Growth Factor A ; Xenograft Model Antitumor Assays

OBJECTIVE: To investigate the current status of antibiotic use for very and extremely low birth weight (VLBW/ELBW) infants in neonatal intensive care units (NICUs) of Hunan Province. METHODS: The use of antibiotics was investigated in multiple level 3 NICUs of Hunan Province for VLBW and ELBW infants born between January, 2017 and December, 2017. RESULTS: The clinical data of 1 442 VLBW/ELBW infants were collected from 24 NICUs in 2017. The median antibiotic use duration was 17 days (range: 0-86 days), accounting for 53.0% of the total length of hospital stay. The highest duration of antibiotic use was up to 91.4% of the total length of hospital stay, with the lowest at 14.6%. In 16 out of 24 NICUs, the antibiotic use duration was accounted for more than 50.0% of the hospitalization days. There were 113 cases with positive bacterial culture grown in blood or cerebrospinal fluid, making the positive rate of overall bacterial culture as 7.84%. The positive rate of bacterial culture in different NICUs was significantly different from 0% to 14.9%. The common isolated bacterial pathogens Klebsiella pneumoniae was 29 cases (25.7%); Escherichia coli 12 cases (10.6%); Staphylococcus aureus 3 cases (2.7%). The most commonly used antibiotics were third-generation of cephalosporins, accounting for 41.00% of the total antibiotics, followed by penicillins, accounting for 32.10%, and followed by carbapenems, accounting for 13.15%. The proportion of antibiotic use time was negatively correlated with birth weight Z-score and the change in weight Z-score between birth and hospital discharge (r=-0.095, -0.151 respectively, P<0.01), positively correlated with death/withdrawal of care (r=0.196, P<0.01). CONCLUSIONS Antibiotics used for VLBW/ELBW infants in NICUs of Hunan Province are obviously prolonged in many NICUs. The proportion of routine use of third-generation of cephalosporins and carbapenems antibiotics is high among the NICUs.
Anti-Bacterial Agents ; Birth Weight ; Humans ; Infant ; Infant, Extremely Low Birth Weight ; Infant, Newborn ; Intensive Care Units, Neonatal ; Surveys and Questionnaires

Objective To study the role of dendritic cells in the function of a recombinant protein TFPR 1 as an adjuvant .Methods Bone marrow cells were collected from four-to five-week-old male BALB/c mice under aseptic conditions, and cultured with complete RPMI 1640 containing rmGM-CSF and rmIL-4 for six days.TFPR1 was added on day 6, and cells were incubated for another 24 hours.LPS was used as positive control , while PBS as negative .The morphology of dendritic cells was observed under an optical microscope and laser confocal microscope , cell surface makers (CD40,CD80,CD86 and MHCⅡ)were detected with flow cytometry, and the cytokines in the supernatant were detected with ELISA.Results Compared with negative control ,dendritic cells incubated with TFPR1 for 24 hours were significantly different in morphology as was observed by optical and laser confocal microscopes , but were similar to positive control .Most of the dendritic cells treated with TFPR 1 showed less adherence and became round , whose podosomes became shorter , and even disappeared .Actin distribution changed from two poles of the cell to the membrane .CD40,CD80, CD86 and MHCⅡon the cell surface were up-regulated on stimulation by TFPR1,as was detected by FACS.These results showed that TFPR1 was capable of promoting dendritic cell maturation .ELISA showed dendritic cells treated with TFPR 1 secreted high levels of cytokines(IL-6, IL-8 and TNF-α).Conclusion TFPR1 is capable of promoting dendritic cell maturation , and activating cells to produce cytokines , indicating that dendritic cells can play an important role in the function of TFPR 1 as a novel ad-juvant .