Bacterial therapy has attracted increasing attention due to its special mechanism and abundant applications. With the flourishing development of synthetic biology, therapeutic genes have been introduced into engineering bacteria to improve their antitumor efficacy. However, it is difficult to spatiotemporally control the expression of these therapeutic genes at the tumor site in vivo, thereby considerably limiting the application of engineered bacteria in tumor treatment. To resolve this problem, we constructed a temperature-responsive bacterial strain capable of triggering the expression of exogenous genes in a laser-controllable way. Noxa, a pro-apoptotic protein, is chosen to test the expression of exogenous protein and its anti-tumor effect in engineered bacteria upon laser irradiation. Firstly, Noxa was fused to the C-terminus of the bacterial outer membrane protein cytolysin A (ClyA), and then the recombinant gene fragment ClyA-Noxa was inserted into the temperature-sensitive plasmid pBV220 and the recombinant plasmid was transformed into non-pathogenic Escherichia coli MG1655. Thus, we constructed the engineering strain (TRB@Noxa) that could express Noxa on the bacterial surface. TRB@Noxa could target and colonize the tumor tissue without causing notable host toxicity. The bacterial infection triggered thrombosis in the tumor tissue, resulting in the darkness of tumor sites. In a xenograft mouse tumor model, our strategy demonstrated precise tumor targeting and strong tumor inhibition. In conclusion, we successfully constructed a new engineering bacterial strain TRB@Noxa. TRB@Noxa combined with photothermal therapy could arrest tumor growth in the absence of photosensitizers, which represents an appealing method for antitumor therapy in the future.
Escherichia coli/radiation effects* ; Animals ; Humans ; Lasers ; Mice ; Proto-Oncogene Proteins c-bcl-2/biosynthesis* ; Neoplasms/therapy* ; Genetic Engineering ; Cell Line, Tumor ; Escherichia coli Proteins/genetics*

Objective:To discuss the suitable concentration of D-galactose(D-gal)and modeling period,and establish its induced aging-related cognitive dysfunction model in the mice,and perform a comprehensive evaluation.Methods:Fifty C57BL/6J mice were randomly divided into control group and 100,200,400,and 800 mg·kg-1 D-gal groups,with 10 mice in each group.The mice in various D-gal groups were subcutaneously injected with the corresponding concentration of D-gal once daily;the mice in control group were injected with an equal volume of normal saline.The body mass and water consumption of the mice in various groups were monitored;forelimb grip strength test and experiment on the ability of pole climbing sports were used to evaluate the motor coordination ability of the mice in various groups;novel object recognition test,Y maze test,and Morris water maze test were used to evaluate the cognitive function of the mice in various groups;HE staining and Nissl staining were used to observe the pathomorphology of brain tissue of the mice in various groups;immunohistochemistry method was used to detect the expression of β-galactosidase(β-gal)protein in brain tissue of the mice in various groups;real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the mRNA expression levels of interleukin(IL)-1β,tumor necrosis factor-α(TNF-α),IL-18,and IL-4 in hippocampus tissue of the mice in various groups;Western blotting method was used to detect the expression levels of β-gal,p53,and p16 proteins in hippocampus tissue of the mice in various groups.Results:The body mass growth trends of the mice in control group and various D-gal groups were consistent and there was no statistically significant difference(P>0.05),and there was no statistically significant difference in water consumption(P>0.05).After 8 weeks of subcutaneous injection of D-gal,compared with control group,the forelimb grip strength values of the mice in 200 and 400 mg·kg?1 D-gal groups were significantly decreased(P<0.05 or P<0.01);the pole-climbing time of the mice in 200 mg·kg?1 D-gal group was significantly prolonged(P<0.05);the recognition indexes of the mice in 200 and 400 mg·kg?1 D-gal groups were significantly decreased(P<0.01);the spontaneous alternation rate of the mice in 100,200,400,and 800 mg·kg?1 D-gal group was significantly decreased(P<0.05 or P<0.01),the escape latency was significantly increased(P<0.05).Spatial probe test showed that compared with control group,the escape latency of the mice in 200 mg·kg?1 D-gal group was significantly increased(P<0.05).The HE staining and Nissl staining results showed that compared with control group,the hippocampus neurons of the mice in 200 mg·kg-1 D-gal group were arranged disorderly,with obvious nuclear pyknosis,nuclear condensation,and abnormal morphology and structure,and the number of Nissl staining positive cells was significantly decreased.The immunohistochemistry results showed that compared with control group,the β-gal expressions in CA1 region,CA3 region,and cortex region of hippocampus tissue of the mice in 200 mg·kg?1 D-gal group were strongly positive.The RT-qPCR results showed that compared with control group,the expression levels of IL-1β,IL-18,and TNF-α mRNA in hippocampus tissue of the mice in 200 mg·kg?1 D-gal group were significantly increased(P<0.05 or P<0.01),and the expression level of IL-4 mRNA was significantly decreased(P<0.01).The Western blotting results showed that compared with control group,the expression levels of β-gal,p53,and p16 proteins in hippocampus tissue of the mice in 200 mg·kg?1 D-gal group were significantly increased(P<0.05 or P<0.01).Conclusion:The aging-related cognitive dysfunction model in the mice can be established by subcutaneous injection of 200 mg·kg?1 D-gal daily for 8 weeks.

The female reproductive system is essential for sustaining reproductive endocrine homeostasis,however,its vulnerability to various endogenous and exogenous insults,including pathological conditions,pharmacological agents,genetic predispositions,and environmental factors,often results in compromised fertility.The existing protective approaches(including surgical interventions,hormonal replacement therapies,and assisted reproductive techniques)are constrained by several limitations,such as adverse therapeutic effects,technical complexities,and their incapacity to reverse ovarian senescence.Artemisinin and its derivatives(ARTs),characterized by their unique endoperoxide bridge configuration,have exhibited outstanding therapeutic performance across multiple domains including malaria treatment,anticancer therapy,inflammation modulation,and parasitic infection control.Emerging research has identified their novel protective capabilities against various reproductive system pathologies.This comprehensive review systematically elucidates the molecular mechanisms underlying artemisinin-based interventions in reproductive pathologies and evaluates their clinical translation prospects,thereby proposing innovative strategies for the development of next-generation fertility-protective agents with enhanced safety and efficacy profiles.

The female reproductive system is essential for sustaining reproductive endocrine homeostasis,however,its vulnerability to various endogenous and exogenous insults,including pathological conditions,pharmacological agents,genetic predispositions,and environmental factors,often results in compromised fertility.The existing protective approaches(including surgical interventions,hormonal replacement therapies,and assisted reproductive techniques)are constrained by several limitations,such as adverse therapeutic effects,technical complexities,and their incapacity to reverse ovarian senescence.Artemisinin and its derivatives(ARTs),characterized by their unique endoperoxide bridge configuration,have exhibited outstanding therapeutic performance across multiple domains including malaria treatment,anticancer therapy,inflammation modulation,and parasitic infection control.Emerging research has identified their novel protective capabilities against various reproductive system pathologies.This comprehensive review systematically elucidates the molecular mechanisms underlying artemisinin-based interventions in reproductive pathologies and evaluates their clinical translation prospects,thereby proposing innovative strategies for the development of next-generation fertility-protective agents with enhanced safety and efficacy profiles.

Abdominal aortic aneurysm (AAA) is a life-threatening large-vessel disease closely associated with immune and inflammation-related mechanisms. During the development of AAA,innate immune cells play a pivotal role in the immune-mediated inflammatory infiltration and destruction of the aortic wall. These cells include neutrophils,monocytes,macrophages,dendritic cells,mast cells,natural killer cells,innate lymphoid cells,and invariant natural killer T cells. Although various immune cells have been progressively identified in the study of AAA,their activation mechanisms and functions remain to be further elucidated. This article summarizes the roles of innate immune cells in the progression of AAA and discusses the regulatory mechanisms of their activation in this disease,providing a theoretical basis for research on AAA progression.

Abdominal aortic aneurysm (AAA) is a life-threatening large-vessel disease closely associated with immune and inflammation-related mechanisms. During the development of AAA,innate immune cells play a pivotal role in the immune-mediated inflammatory infiltration and destruction of the aortic wall. These cells include neutrophils,monocytes,macrophages,dendritic cells,mast cells,natural killer cells,innate lymphoid cells,and invariant natural killer T cells. Although various immune cells have been progressively identified in the study of AAA,their activation mechanisms and functions remain to be further elucidated. This article summarizes the roles of innate immune cells in the progression of AAA and discusses the regulatory mechanisms of their activation in this disease,providing a theoretical basis for research on AAA progression.

BACKGROUND: Despite the progress in perinatal-neonatal medicine, complications of extremely preterm infants continue to constitute the major adverse outcomes in neonatal intensive care unit. Human umbilical cord Wharton’s Jellyderived mesenchymal stem cells (HUMSCs) may offer new hope for the treatment of intractable neonatal disorders. This study will explore the functional differences of HUMSCs between extremely preterm and term infants. METHODS: UMSCs from 5 extremely preterm infants(weeks of gestation: 22+5 w,24+4 w,25+3 w,26 w,28 w) and 2 term infants(39 w,39+2 w) were isolated, and mesenchymal markers, pluripotent genes, proliferation rate were analyzed.HUVECs were injured by treated with LPS and repaired by co-cultured with HUMSCs of different gestational ages. RESULTS: All HUMSCs showed fibroblast-like adherence to plastic and positively expressed surface marker of CD105,CD73 and CD90, but did not expressed CD45,CD34,CD14,CD79a and HLA-DR; HUMSCs in extremely preterm exhibited significant increase in proliferation as evidenced by CCK8, pluripotency markers OCT-4 tested by RT-PCR also showed increase. Above all, in LPS induced co-cultured inflame systerm, HUMSCs in extremely preterm were more capable to promote wound healing and tube formation in HUVEC cultures, they promoted TGFb1 expression and inhibited IL6 expression. CONCLUSIONS Our results suggest that HUMSCs from extremely preterm infants may be more suitable as candidates in cell therapy for the preterm infants.

Objective:To compare the efficacy and safety of insulin degludec and insulin glargine U100 in patients with type 2 diabetes mellitus.Methods:This study was a retrospective cohort study. The subjects were patients with type 2 diabetes mellitus who were hospitalized in 13 3A-level general hospitals in Shandong Province from September 2018 to December 2021. According to the type of basal insulin used, the patients were divided into insulin degludec group and insulin glargine U100 group. The basic information and laboratory test results in patients in the 2 groups were collected, the differences of fasting blood glucose level and incidence of hypoglycemia between the 2 groups were compared. The patients with complete blood glucose monitoring data in the 2 groups were selected and their blood glucose fluctuations were compared.Results:A total of 1 152 patients were entered in the study, including 552 patients in the insulin degludec group and 600 patients in the insulin glargine U100 group. The difference in the basic conditions in patients in the 2 groups was not statistically significant (all P>0.05). After treatment, the fasting blood glucose levels in patients in the 2 groups were lower than those before treatment, with statistically significant differences [10.2 (8.8, 12.5) mmol/L vs. 7.5 (6.6, 8.7) mmol/L, Z=-19.443, P<0.001; 10.0 (8.6, 11.7) mmol/L vs. 7.8 (6.6, 9.0) mmol/L, Z=-15.449, P<0.001], but the difference in fasting blood glucose levels between the 2 groups after treatment was not statistically significant ( Z=-1.427, P>0.05). The incidence of hypoglycemia in the insulin degludec group was lower than that in the insulin glargine U100 group [1.09% (6/552) vs. 2.83% (17/600), Z=4.481, P=0.032]. The intraday blood glucose standard deviation, maximum blood glucose fluctuation range, postprandial blood glucose fluctuation range, and average blood glucose fluctuation range in patients with complete blood glucose monitoring data in the insulin degludec group were significantly lower than those in the insulin glargine U100 group [(1.7±0.6) mmol/L vs. (2.4±1.0) mmol/L, (4.5±1.6) mmol/L vs. (6.7±2.9) mmol/L, (1.8±1.0) mmol/L vs. (3.3±1.2) mmol/L, (2.9±1.3) mmol/L vs. (4.6±2.1) mmol/L; all P<0.001]. Conclusion:The efficacy of insulin degludec in the treatment of type 2 diabetes mellitus is equivalent to that of insulin glargine U100, but the risk of hypoglycemia and blood glucose fluctuation is lower.

Objective:To compare the efficacy and safety of insulin degludec and insulin glargine U100 in patients with type 2 diabetes mellitus.Methods:This study was a retrospective cohort study. The subjects were patients with type 2 diabetes mellitus who were hospitalized in 13 3A-level general hospitals in Shandong Province from September 2018 to December 2021. According to the type of basal insulin used, the patients were divided into insulin degludec group and insulin glargine U100 group. The basic information and laboratory test results in patients in the 2 groups were collected, the differences of fasting blood glucose level and incidence of hypoglycemia between the 2 groups were compared. The patients with complete blood glucose monitoring data in the 2 groups were selected and their blood glucose fluctuations were compared.Results:A total of 1 152 patients were entered in the study, including 552 patients in the insulin degludec group and 600 patients in the insulin glargine U100 group. The difference in the basic conditions in patients in the 2 groups was not statistically significant (all P>0.05). After treatment, the fasting blood glucose levels in patients in the 2 groups were lower than those before treatment, with statistically significant differences [10.2 (8.8, 12.5) mmol/L vs. 7.5 (6.6, 8.7) mmol/L, Z=-19.443, P<0.001; 10.0 (8.6, 11.7) mmol/L vs. 7.8 (6.6, 9.0) mmol/L, Z=-15.449, P<0.001], but the difference in fasting blood glucose levels between the 2 groups after treatment was not statistically significant ( Z=-1.427, P>0.05). The incidence of hypoglycemia in the insulin degludec group was lower than that in the insulin glargine U100 group [1.09% (6/552) vs. 2.83% (17/600), Z=4.481, P=0.032]. The intraday blood glucose standard deviation, maximum blood glucose fluctuation range, postprandial blood glucose fluctuation range, and average blood glucose fluctuation range in patients with complete blood glucose monitoring data in the insulin degludec group were significantly lower than those in the insulin glargine U100 group [(1.7±0.6) mmol/L vs. (2.4±1.0) mmol/L, (4.5±1.6) mmol/L vs. (6.7±2.9) mmol/L, (1.8±1.0) mmol/L vs. (3.3±1.2) mmol/L, (2.9±1.3) mmol/L vs. (4.6±2.1) mmol/L; all P<0.001]. Conclusion:The efficacy of insulin degludec in the treatment of type 2 diabetes mellitus is equivalent to that of insulin glargine U100, but the risk of hypoglycemia and blood glucose fluctuation is lower.

Objective:To investigate the incidence and trend of severe postpartum hemorrhage (sPPH) in China, and to provide basic data for the development and evaluation of sPPH prevention and control strategy.Methods:Obstetric data was extracted from annual national representative sampling surveys based on the National Clinical Improvement System. From 2016 to 2019, 2 978, 3 400, 4 576 and 4 594 maternity hospitals with sPPH cases were included for statistics. The annual incidence of sPPH was calculated according to province and type of medical institutions and generalized linear model was emplyed to identify the determinants affecting sPPH incidence.Results:In China, sPPH incidence increased from 0.62% in 2016 to 0.93% in 2018, and was 0.92% in 2019. Eighteen provinces had an inverted U-shaped trend of sPPH over time and most of them had the highest incidence in 2018; ten provinces had an upward trend of sPPH and 3 provinces had a U-shaped trend. In 2019, the top five provinces with the highest sPPH incidence were Yunnan (1.88%), Beijing (1.45%), Jiangsu (1.31%), Guizhou (1.26%), and Ningxia Hui Autonomous Region (1.22%); the top five provinces with the lowest incidence were Henan (0.55%), Jiangxi (0.60%), Inner Mongolia Autonomous Region (0.64%), Liaoning (0.64%) and Gansu (0.69%). In 2019, the sPPH incidence in different types of medical institutions were as follows: tertiary public general hospital (1.15%), tertiary public specialized hospital (1.02%), secondary public general hospital (0.81%), private hospital (0.61%) and secondary public specialized hospital (0.58%). sPPH incidence was positively associated with proportion of twin pregnancies, macrosomia, primipara, and puerpera aged ≥35 years in maternity hospitals ( P<0.05). Conclusions:sPPH incidence generally showes an increasing trend from 2016 and is stable at a high level in recent two years in China. It is warranted to further strengthen the monitoring of postpartum hemorrhage, and improve the capability of hierarchical management and treatment in maternity institutions and regions, in order to reduce sPPH incidence and maternal mortality.