OBJECTIVE To investigate the ameliorative effect and potential mechanism of imperatorin （IMP） on doxorubicin （DOX） resistance in breast cancer. METHODS The effects of maximum non-toxic concentration （100 μg/mL） of IMP combined with different concentrations of DOX （12.5， 25， 50， 75， 100 μg/mL） on the proliferation of MCF-7/DOX cells were determined by MTT method. MCF-7/DOX cells were divided into blank control group （1‰ dimethyl sulfoxide）， DOX group （50 μg/mL）， IMP+DOX group （100 μg/mL IMP+50 μg/mL DOX） and IMP group （100 μg/mL）. mRNA and protein expressions of multidrug resistance protein 1 （MDR1） and multidrug resistance-associated protein 1 in each group were measured. The relevant pathways and targets involved in the improvement of DOX resistance in breast cancer cells by IMP were screened and validated by using transcriptome sequencing technology， along with gene ontology （GO） enrichment analyses and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analyses. RESULTS Compared with DOX alone， the combination of IMP and DOX reduced the half inhibitory concentration of DOX on MCF-7/DOX cells from 81.965 μg/mL to 43.170 μg/mL， the reverse fold was 1.90， and the mRNA expression of MDR1 was significantly down-regulated （P＜0.05）. The results of GO enrichment analyses and KEGG pathway enrichment analyses indicated that the reversal of DOX resistance in breast cancer by IMP was mainly associated with the regulation of biological processes such as detoxification， multiple biological processes， and cell killing. The main pathway involved was the p53 signaling pathway， and the key targets mainly included constitutively photomorphogenic protein 1 （COP1）， cyclin E1 （CCNE1）， growth arrest and DNA damage-inducible protein 45A E-mail：tangxilan1983@163.com （GADD45A） and GADD45B. The results of the verification experiments showed that compared with DOX group， there was a trend of up-regulation of COP1 mRNA， and significant down- regulation of CCNE1， GADD45A， and GADD45B mRNA expression in IMP+DOX group （P＜0.05）. CONCLUSIONS The effect of IMP in ameliorating DOX resistance in breast cancer is related to its regulation of COP1， CCNE1， GADD45A and GADD45B targets in the p53 signaling pathway.

The complex anatomical structure and physiological barriers of the eye present substantial challenges for local drug delivery, leading to suboptimal ocular drug bioavailability, which typically remains below 5% in conventional ophthalmic formulations. Frequent or high-dose administration not only increases the treatment burden but also heightens the risk of both local and systemic adverse effects. Liposomes, as an advanced drug delivery system, enhance ocular bioavailability through their biocompatibility and targeted delivery properties. Recent innovations in surface modification and functionalization have further enhanced their ability to overcome ocular barriers and facilitate controlled drug release. Liposome-based formulations have demonstrated significant therapeutic potential for diseases such as glaucoma and dry eye syndrome. Drawing on the research advancements over the past 5 a, this article systematically reviews the innovative design strategies and applications of liposomes in ocular drug delivery, with the aim of providing theoretical basis and technical reference for the development of new ophthalmic drugs.

Objective:To investigate the effect of sodium tanshinone ⅡA sulfonate (STS) on pyroptosis of human umbilical vein endothelial cells (HUVECs) induced by H 2O 2 and its possible mechanism. Methods:From November 2021 to September 2022, HUVECs were used as the research subjects at Wuxi Ninth People’s Hospital. The experiment was divided into four groups: the blank control group (normal condition), blank + STS group, H 2O 2 group and H 2O 2 + STS group. When the cells reached 80% fusion, 500.00 μmol/L of H 2O 2 was added to H 2O 2 group and H 2O 2 + STS group for 3 hours, and then the medium containing 500.00 μmol/L H 2O 2 was removed. After that, the blank+ STS group and the H 2O 2+ STS group were each supplemented with 5.00 μg/ml of STS and co-cultured with HUVECs for 24 hours. CCK-8 was used to assess the impact of STS at various concentrations (0.00, 0.05, 0.50, 5.00, 50.00, 500.00 μg/ml) on the proliferation of HUVECs. DNA damage-positive cells were detected with TUNEL staining. The expression of NOD-like receptor protein 3 (NLRP3) was detected using real-time PCR (RT-PCR) to investigate the optimal concentration of pyroptosis induced by H 2O 2. A detection kit was used to measure the expression of reactive oxygen species (ROS) induced by H 2O 2. The effect of STS on the migration and tube formation of HUVECs during pyroptosis was examined using a cell scratch test and a matrix gel tube formation test. The expressions of NLRP3, caspase-1, interleukin-18, and interleukin-1β were detected using RT-PCR and Western blotting. Repeated measures ANOVA was used to compare the concentrations at different time points, t-tests were used to compare data between two groups, and one-way ANOVA was used to compare data between multiple groups. P<0.05 was considered statistically significant. Results:STS below 50.00 μg/ml had no effect on the proliferation of HUVECs, while 500.00 μmol/L H 2O 2 had the most significant effect on inducing pyroptosis in HUVECs. TUNEL staining showed that compared with the control group, the number of TUNEL-positive cells in H 2O 2 group was significantly increased, and the difference was statistically significant ( P<0.01). However, there was no significant difference in the number of TUNEL-positive cells in the H 2O 2+ STS group ( P>0.05). The results of ROS detection showed that compared with the H 2O 2 group, intracellular ROS levels in the H 2O 2+ STS group was significantly decreased, and the difference was statistically significant ( P<0.01). Cell scratch and tube formation in vitro experiments showed that compared with the control group, cell mobility and tube formation ability were significantly decreased in the H 2O 2 group (all P<0.01), and there was no statistical significance in the H 2O 2+ STS group (all P>0.05). RT-PCR and Western blotting results showed that, compared with the H 2O 2 group, the expression of pyroptosis-related factors in the H 2O 2+ STS group was significantly decreased (all P<0.05). Conclusion:STS can inhibit the excessive production of ROS, promote the cell migration and tubular formation of HUVECs after pyroptosis induction, and alleviate H 2O 2-induced pyroptosis of HUVECs, thereby promoting angiogenesis.

Objective:To investigate the effect of sodium tanshinone ⅡA sulfonate (STS) on pyroptosis of human umbilical vein endothelial cells (HUVECs) induced by H 2O 2 and its possible mechanism. Methods:From November 2021 to September 2022, HUVECs were used as the research subjects at Wuxi Ninth People’s Hospital. The experiment was divided into four groups: the blank control group (normal condition), blank + STS group, H 2O 2 group and H 2O 2 + STS group. When the cells reached 80% fusion, 500.00 μmol/L of H 2O 2 was added to H 2O 2 group and H 2O 2 + STS group for 3 hours, and then the medium containing 500.00 μmol/L H 2O 2 was removed. After that, the blank+ STS group and the H 2O 2+ STS group were each supplemented with 5.00 μg/ml of STS and co-cultured with HUVECs for 24 hours. CCK-8 was used to assess the impact of STS at various concentrations (0.00, 0.05, 0.50, 5.00, 50.00, 500.00 μg/ml) on the proliferation of HUVECs. DNA damage-positive cells were detected with TUNEL staining. The expression of NOD-like receptor protein 3 (NLRP3) was detected using real-time PCR (RT-PCR) to investigate the optimal concentration of pyroptosis induced by H 2O 2. A detection kit was used to measure the expression of reactive oxygen species (ROS) induced by H 2O 2. The effect of STS on the migration and tube formation of HUVECs during pyroptosis was examined using a cell scratch test and a matrix gel tube formation test. The expressions of NLRP3, caspase-1, interleukin-18, and interleukin-1β were detected using RT-PCR and Western blotting. Repeated measures ANOVA was used to compare the concentrations at different time points, t-tests were used to compare data between two groups, and one-way ANOVA was used to compare data between multiple groups. P<0.05 was considered statistically significant. Results:STS below 50.00 μg/ml had no effect on the proliferation of HUVECs, while 500.00 μmol/L H 2O 2 had the most significant effect on inducing pyroptosis in HUVECs. TUNEL staining showed that compared with the control group, the number of TUNEL-positive cells in H 2O 2 group was significantly increased, and the difference was statistically significant ( P<0.01). However, there was no significant difference in the number of TUNEL-positive cells in the H 2O 2+ STS group ( P>0.05). The results of ROS detection showed that compared with the H 2O 2 group, intracellular ROS levels in the H 2O 2+ STS group was significantly decreased, and the difference was statistically significant ( P<0.01). Cell scratch and tube formation in vitro experiments showed that compared with the control group, cell mobility and tube formation ability were significantly decreased in the H 2O 2 group (all P<0.01), and there was no statistical significance in the H 2O 2+ STS group (all P>0.05). RT-PCR and Western blotting results showed that, compared with the H 2O 2 group, the expression of pyroptosis-related factors in the H 2O 2+ STS group was significantly decreased (all P<0.05). Conclusion:STS can inhibit the excessive production of ROS, promote the cell migration and tubular formation of HUVECs after pyroptosis induction, and alleviate H 2O 2-induced pyroptosis of HUVECs, thereby promoting angiogenesis.

Objective To analyze the blindness and visual impairment attributed to myopic maculopathy in highly myopic patients based on the ATN classification system,as well as associated risk factors.Methods In this retrospective case-control study,clinical data of 642 adult patients(642 eyes)with high myopia admitted to the Department of Fundus Disease,Chengdu Bright Eye Hospital from January 2022 to September 2023 were collected and analyzed.Comprehensive ophthalmic examinations were conducted for all patients.Myopic maculopathy in patients with high myopia was diagnosed and graded according to the ATN classification system.The patients were divided into the blindness or visual impairment group and the non or mild visual impairment group based on the WHO diagnostic criteria for blindness and visual impair-ment.Multivariate Logistic regression was utilized to analyze the risk factors for blindness or visual impairment in patients with high myopia.Results Among the 642 eyes,myopic maculopathy was identified in 355 eyes(55.30％).Of these,there were 330 eyes(51.40％)with myopic atrophy maculopathy(A2 and above),137 eyes(21.34％)with myopic trac-tion maculopathy,and 82 eyes(12.77％)with myopic neovascular maculopathy.The percentages of blindness and visual impairment were 2.02％(95％CI:0.93％-3.11％)and 8.41％(95％CI:6.26％-10.56％),respectively.Multivariate Lo-gistic regression analysis showed that older age,longer axial length and higher grade of myopic atrophy maculopathy were independent risk factors for blindness or visual impairment in patients with high myopia(all P＜0.05).Conclusion The ATN classification system can comprehensively reflect the disease severity and visual impairment of patients with myopic maculopathy.Older age,longer axial length and higher grade of myopic atrophy maculopathy are independent risk factors for blindness or visual impairment in patients with high myopia.

Objective:To explore the efficacy of subcutaneous injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) in preventing invasive fungal disease (IFD) in patients with multiple myeloma (MM).Methods:The clinical data of 222 patients who were admitted to the Second Hospital of Harbin Medical University from January 2015 to June 2021 were retrospectively analyzed. The patients was given GM-CSF (3-5 μg·kg -1·d -1, GM-CSF group) or granulocyte colony-stimulating factor (G-CSF, 2-5 μg·kg -1·d -1, G-CSF group) when neutrophils (ANC) ≤1.5×10 9/L after induction chemotherapy. Patients were discontinued when white blood cell count (WBC) ≥10.0×10 9/L. The incidence of IFD (including confirmed, clinical and proposed diagnosis) and breakthrough invasive fungal infections was compared between the two groups. Results:The incidence of IFD was 8.1% (18/222) in all patients. The incidence of IFD was 3.5% (3/85) and 10.9% (15/137) in the GM-CSF and G-CSF groups, respectively, and the difference between the two groups was statistically significant ( χ2 = 3.88, P = 0.049). In 9 patients of GM-CSF group receiving fungal infection prophylaxis and in 15 patients of G-CSF group receiving fungal infection prophylaxis, the incidence of breakthrough invasive fungal infections was 0 and 7 cases, respectively, and the difference between the two groups was statistically significant ( P = 0.022). Conclusions:GM-CSF application in MM patients can reduce the incidence of IFD and breakthrough invasive fungal infections.

Objective:To study the clinical characteristics of different types of neonatal sepsis.Methods:From January 2012 to December 2019, neonates with confirmed sepsis from 5 neonatal centers of central-south China were reviewed. The neonates were assigned into early-onset sepsis (EOS) and late-onset sepsis (LOS) group, and the latter was further subgrouped into hospital-acquired LOS (hLOS) group and community-acquired LOS (cLOS) group. The etiological and clinical characteristics were analyzed. SPSS 26.0 was used for statistical analysis.Results:A total of 580 neonates were enrolled, including 286 (49.3%) in the EOS group and 294 (50.7%) in the LOS group. In LOS group, 147 were in hLOS group and 147 were in cLOS group. The gestational age and birth weight of hLOS group were significantly lower than the other two groups [(32.7±3.6) weeks vs. (37.1±3.7) weeks and (37.7±3.0) weeks, (1 810±717) g vs. (2 837±865) g and (3 024±710) g] ( P<0.05). The common pathogens in EOS and cLOS groups were coagulase-negative staphylococci and Escherichia coli, while Klebsiella pneumoniae was common in hLOS group. Carbapenems usage in the hLOS group was significantly higher than the other two groups [62.6% vs. 28.7% and 16.2%] ( P<0.05). Antibiotics duration in the hLOS group was longer than the other two groups [19 (14, 27) d vs. 15 (12, 20) d and 14 (12, 19) d] ( P<0.05). Conclusions:The clinical characteristics of neonatal sepsis vary among different types of infections, and it is necessary to establish appropriate prevention, control, diagnosis and treatment protocols.

This study aimed to observe the protective effect of momordicine I, a triterpenoid compound extracted from momordica charantia L., on isoproterenol (ISO)-induced hypertrophy in rat H9c2 cardiomyocytes and investigate its potential mechanism. Treatment with 10 μM ISO induced cardiomyocyte hypertrophy as evidenced by increased cell surface area and protein content as well as pronounced upregulation of fetal genes including atrial natriuretic peptide, β-myosin heavy chain, and α-skeletal actin; however, those responses were markedly attenuated by treatment with 12.5 μg/ml momordicine I. Transcriptome experiment results showed that there were 381 and 447 differentially expressed genes expressed in comparisons of model/control and momordicine I intervention/model, respectively. GO enrichment analysis suggested that the anti-cardiomyocyte hypertrophic effect of momordicine I may be mainly associated with the regulation of metabolic processes. Based on our transcriptome experiment results as well as literature reports, we selected glycerophospholipid metabolizing enzymes group VI phospholipase A 2 (PLA2G6) and diacylglycerol kinase ζ (DGK-ζ) as targets to further explore the potential mechanism through which momordicine I inhibited ISO-induced cardiomyocyte hypertrophy.Our results demonstrated that momordicine I inhibited ISO-induced upregulations of mRNA levels and protein expressions of PLA2G6 and DGK-ζ. Collectively, momordicine I alleviated ISO-induced cardiomyocyte hypertrophy, which may be related to its inhibition of the expression of glycerophospholipid metabolizing enzymes PLA2G6 and DGK-ζ.

OBJECTIVE: To analyze the clinical features and genotype of a child with Schmid type metaphyseal chondrodysplasia. METHODS: Clinical data of the child and her parents was collected. The child was subjected to high-throughput sequencing, and candidate variant was verified by Sanger sequencing of her family members. RESULTS: Whole exome sequencing revealed that the child has harbored a heterozygous c.1772G>A (p.C591Y) variant of the COL10A1 gene, which was not found in either of her parents. The variant was not found in the HGMD and ClinVar databases, and was rated as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). CONCLUSION The heterozygous c.1772G>A (p.C591Y) variant of the COL10A1 gene probably underlay the Schmid type metaphyseal chondrodysplasia in this child. Genetic testing has facilitated the diagnosis and provided a basis for genetic counselling and prenatal diagnosis for this family. Above finding has also enriched the mutational spectrum of the COL10A1 gene.
Humans ; Child ; Female ; Mutation ; Osteochondrodysplasias/diagnosis* ; Heterozygote ; Molecular Biology

Sex difference has shown in the arthritis diseases in human population and animal models. We investigate how the sex and symmetry vary among mouse models with different genomic backgrounds. Disease data of sex and limbs accumulated in the past more than two decades from four unique populations of murine arthritis models were analyzed. They are (1) interleukin-1 receptor antagonist (IL-1ra) deficient mice under Balb/c background (Balb/c KO); (2) Mice with collagen II induced arthritis under DBA/1 background; (3) Mice with collagen II induced arthritis under C57BL/6 (B6) background and (4) A F2 generation population created by Balb/c KO X DBA/1 KO.Our data shows that there is a great variation in sexual dimorphism for arthritis incidence and severity of arthritis in mice harboring specific genetic modifications. For a F2 population, the incidence of arthritis was 57.1% in female mice and 75.6% in male mice. There was a difference in severity related to sex in two populations: B6.DR1/ B6.DR4 (P < 0.001) and F2 (P = 0.023) There was no difference Balb/c parental strain or in collagen-induced arthritis (CIA) in DBA/1 mice. Among these populations, the right hindlimbs are significantly higher than the scores for the left hindlimbs in males (P < 0.05). However, when examining disease expression using the collagen induced arthritis model with DBA/1 mice, sex-dimorphism did not reach statistical significance, while left hindlimbs showed a tendency toward greater disease expression over the right. Sexual dimorphism in disease expression in mouse models is strain and genomic background dependent. It sets an alarm that potential variation in sexual dimorphism among different racial and ethnic groups in human populations may exist. It is important to not only include both sexes and but also pay attention to possible variations caused by disease expression and response to treatment in all the studies of arthritis in animal models and human populations.