With the widespread use of antibiotics, drug-resistant bacterial infections have become a significant threat to human health. Finding new antibacterial strategies that can effectively control drug-resistant bacterial infections has become an urgent task. Unlike small molecule drugs that target bacterial proteins, antisense oligonucleotide (ASO) can target genes related to bacterial resistance, pathogenesis, growth, reproduction and biofilm formation. By regulating the expression of these genes, ASO can inhibit or kill bacteria, providing a novel approach for the development of antibacterial drugs. To overcome the challenge of delivering antisense oligonucleotide into bacterial cells, various drug delivery systems have been applied in this field, including cell-penetrating peptides, lipid nanoparticles and inorganic nanoparticles, which have injected new momentum into the development of antisense oligonucleotide in the antibacterial realm. This review summarizes the current development of small nucleic acid drugs, the antibacterial mechanisms, targets, sequences and delivery vectors of antisense oligonucleotide, providing a reference for the research and development of antisense oligonucleotide in the treatment of bacterial infections.

ObjectiveTo investigate the features of serum HBV RNA in different stages of the natural history of chronic hepatitis B virus （HBV） infection without antiviral treatment， as well as its correlation with serum HBV DNA and HBsAg. MethodsA total of 306 treatment-naïve patients with chronic HBV infection who attended Department of Infections Diseases and Hepatoloty， the Second Hospital of Shandong University from January 2023 to June 2024 were divided into six groups based on the different stages of natural history， i.e.， HBeAg-positive chronic HBV infection group with 29 patients， HBeAg-positive chronic hepatitis B （CHB） group with 107 patients， HBeAg-negative chronic HBV infection group with 18 patients， HBeAg-negative CHB group with 60 patients， HBeAg-positive indeterminate-phase chronic HBV infection group with 7 patients， and HBeAg-negative indeterminate-phase chronic HBV infection group with 85 patients. Real-time isothermal RNA amplification was used to measure serum high-sensitivity HBV RNA. The Kruskal-Wallis H test was used for comparison between multiple groups of continuous data， while the Mann-Whitney U test was used for comparison between two groups. The Spearman method was used to investigate the correlation of HBV RNA with HBV DNA and HBsAg. ResultsThe HBeAg-positive chronic HBV infection group showed the highest level of serum HBV RNA ［7.5 （7.4‍ ‍—‍ ‍7.9） log₁₀ copies/mL］， followed by the HBeAg-positive CHB group ［7.4 （6.4‍ ‍—‍ ‍7.9） log₁₀ copies/mL］， the HBeAg-negative CHB group ［4.5 （3.0‍ ‍—‍ ‍5.7） log₁₀ copies/mL］， and the HBeAg-negative chronic HBV infection group ［1.0 （1.0‍ ‍—‍ ‍2.0） log₁₀ copies/mL］； the HBeAg-positive indeterminate-phase chronic HBV infection group had a serum HBV RNA level of 3.9 （3.7‍ ‍—‍ ‍5.7） log₁₀ copies/mL， and the HBeAg-negative indeterminate-phase chronic HBV infection group had a serum HBV RNA level of 2.0 （1.0‍ ‍—‍ ‍3.0） log₁₀ copies/mL； there was a significant difference in serum HBV RNA level between the six groups （H=830.770， P<0.001）. There was a significant difference in HBV RNA level between the HBeAg-positive chronic HBV infection group and all the other groups except the HBeAg-positive CHB group （all P<0.001）. In the 306 patients with HBV infection， HBV RNA was strongly correlated with HBV DNA （r=0.92， P<0.001） and was moderately correlated with HBsAg （r=0.67， P<0.001）. The correlation between serum HBV RNA and HBsAg in HBeAg-positive patients （r=0.61， P<0.001） was stronger than that in HBeAg-negative patients （r=0.31， P<0.001）. For the patients with HBeAg-positive chronic HBV infection， the male patients with ALT>30 U/L and the female patients with ALT>19 U/L had a significantly lower serum HBV RNA level than the male patients with ALT≤30 U/L and the female patients with ALT≤19 U/L （P<0.001）， and there was no significant difference in serum HBV RNA level between the latter group of patients and the HBeAg-positive CHB group （P>0.05）. ConclusionIn patients with chronic HBV infection who do not receive antiviral therapy， there is a difference in serum HBV RNA level in different stages of natural history， and serum HBV RNA level has the strongest correlation with HBV DNA and a relatively weak correlation with HBsAg. In patients with HBeAg-positive chronic HBV infection， serum HBV RNA level in male patients with ALT>30 U/L and female patients with ALT>19 U/L are in the transition stage between HBeAg-positive chronic HBV infection and HBeAg-positive CHB.

ObjectiveTo investigate the potential machanism of Xiaozhong Zhitong Mixture （消肿止痛合剂， XZM） in the treatment of diabetes foot ulcer （DFU）. MethodsFifty SD rats were randomly divided into blank group， model group， XZM group， inhibitor group， XZM plus inhibitor group （combination group）， with 10 rats in each group. Except for the blank group， rats were fed with high-sugar， high-fat， high-cholesterol diet， intraperitoneally injected with streptozotocin， and subjected to skin defect to establish DFU model. After successful modeling， the XZM group and the combination group were given 1 ml/（100 g·d）of XZM by gavage， while the blank group， model group， and inhibitor group were all given an equal volume of 0.9% sodium chloride injection by gavage. Thirty minutes later， the inhibitor group and the combination group were intraperitoneally injected with 5 mg/（kg·d） of Notch1 inhibitor DAPT. All groups were treated once a day. After 14 days of administration， the skin tissue from the dorsal foot of the blank group rats and wound tissue from the other groups were collected. The pathological changes of granulation tissue in the wound were detected using hematoxylin eosin （HE） staining. The microvascular density （MVD） in wounds was detected through immunohistochemical staining. Real time fluorescence quantitative polymerase chain reaction （RT-PCR） and western blotting were used to detect the mRNA and protein levels of Notch1 homolog （Notch1）， Delta-like ligand 4 （Dll4）， Delta-like ligand 4 （VEGF）， and angiopoietin 2 （Ang-2）， respectively. ResultsHistological results showed that the epidermal structure in the dorsal foot skin tissue of the rats in the blank group was intact. In the wound tissue of the model group， the epidermis exhibited excessive keratinization， vacuolar cytoplasm， and a large number of inflammatory cells infiltrating the tissue， while in the XZM group， a large amount of scab formation was observed in the epidermis， with no significant inflammatory cell infiltration and a noticeable increase in fibroblasts. In the combination group and the inhibitor group， partial epidermal scab formation was observed in the wound tissue with a small amount of inflammatory cell infiltration. Compared to those in the blank group， the MVD in the wound tissue increased in the model group， as well as the mRNA expression and protein levels of Notch1 and Dll4， while VEGFA and Ang-2 mRNA expression and protein levels significantly decreased （P＜0.05 or P＜0.01）. Compared to those in the model group， the MVD in the wound tissue of all medication groups significantly increased， and the mRNA and protein levels of Notch1 and Dll4 decreased， while VEGFA and Ang-2 mRNA expression and protein levels increased （P＜0.05 or P＜0.01）. Compared to the XZM group， the inhibitor group and the combination group showed decreased MVD in wound tissue， increased Notch1 and Dll4 mRNA and protein levels， and decreased expression of VEGFA and Ang-2 mRNA and proteins （P＜0.05 or P＜0.01）. ConclusionXZM can effectively promote wound healing in DFU rats， and its mechanism of action may be related to the inhibition of Dll4/Notch1 signaling pathway in the wound tissue， therey promoting angiogenesis.

Objective: To analyze the relationship between body mass index(BMI) during pre pregnancy, maternal lipid levels during early pregnancy and childhood overweight and obesity, as well as the mediating role of maternal lipid levels during early pregnancy in pre pregnancy BMI and childhood overweight and obesity, providing scientific evidence for developing obesity prevention strategies in preschool children. Methods: Using data from Peking University Birth Cohort in Tongzhou (PKUBC-T) collected between June 2018 and September 2022, the study included 1 292 mother-child pairs. Participants were stratified into two groups based on children s BMI Z scores at age 3: an overweight/obesity risk group (BMI Z >1, n =173) and a non overweight/obesity risk group (BMI Z ≤1, n =1 119).Multivariate Logistic regression was conducted to analyze the associations between pre pregnancy BMI, maternal lipid levels[total cholesterol(TC),triglyceride（TG）,high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),TC/HDL-C,TG/HDL-C,LDL-C/HDL-C] during early pregnancy and childhood overweight and obesity. The mediating effect of maternal lipid levels during early pregnancy on pre pregnancy BMI and childhood overweight and obesity was further explored. Results: There were statistically significant differences in pregnancy BMI levels, early pregnancy blood LDL-C ,TC/HDL-C,LDL-C/HDL-C levels between the overweight and obesity risk group and the non overweight and obesity risk group ( χ 2/Z =19.01, 2.48, 2.48, 2.71, all P <0.05). Multivariate Logistic regression analysis showed that pre pregnancy BMI, LDL-C, TC/HDL-C and LDL-C/HDL-C in early pregnancy were significantly associated with childhood overweight and obesity ( OR =1.09, 1.42, 1.49, 1.60, all P <0.05). LDL-C, TC/HDL-C and LDL-C/HDL-C in early pregnancy played a significant mediating role on pre pregnancy BMI and childhood obesity and the mediating effects accounted for 7.3%, 10.2%, 23.5% of the total effects, respectively (all P <0.05). Conclusions Maternal hyperlipidemia during early pregnancy partially mediated the association between pre pregnancy obesity and childhood obesity. Both pre pregnancy obesity and maternal hyperlipidemia during early pregnancy are risk factors for obesity in preschool children.

ObjectiveTo observe the effect of Banxia Xiexintang （BXT） on the proliferation of human gastric cancer HGC-27， MKN-45， and AGS cells and its mechanism. MethodCell counting kit-8 （CCK-8） was used to detect the effects of different concentrations of BXT-containing serum （5%， 10%， and 20%） on the proliferation of HGC-27， MKN-45， and AGS cells. A mitochondrial membrane potential probe （TMRE） was used to detect the expression of mitochondrial membrane potential in cells. A kit was used to detect iron ion （Fe²⁺） content， lipid peroxide （LPO）， and superoxide dismutase （SOD） activity. Western blot was used to detect the protein expression levels of glycogen synthase3β （GSK3β）， phosphorylated GSK3β （p-GSK3β）， nuclear factor E₂ related factor 2 （Nrf2）， and glutathione peroxidase 4 （GPX4）. The real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of member 11 of the cystine/glutamic acid reverse transporter solute vector family 7 （SLC7A11）， member 2 of the heavy chain solute vector family 3 （SLC3A2）， transferrin receptor 3 （TFRC）， and tumor protein （TP）53. ResultCCK-8 results showed that BXT and capecitabine could significantly reduce the survival rate of three kinds of gastric cancer cells after treatment with drug-containing serum for 24 h （P<0.01）. After 48 h of intervention with drug-containing serum， the survival rate of three kinds of gastric cancer cells was significantly decreased in both the capecitabine group and the BXT group compared with the blank group. The BXT group was dose-dependent， with 20% BXT having the most significant effect （P<0.01）. In terms of biochemical indicators of ferroptosis， compared with the blank group， BXT and capecitabine significantly decreased the expression of mitochondrial membrane potential （P<0.01） and SOD activity （P<0.01） and significantly increased the contents of LPO and Fe²⁺ （P<0.01）， so as to improve the sensitivity of gastric cancer cells to ferroptosis. In terms of the Nrf2/GPX4 pathway， compared with the blank group， the BXT group could reduce the protein expressions of p-GSK3β， Nrf2， and GPX4 （P<0.01） in gastric cancer cells and increase mRNA expressions of SLC7A11 and SLC3A2 （P<0.05）. It could also increase the protein expression of GSK3β （P<0.01） and mRNA expression of TP53 and TFRC （P<0.05， P<0.01） in gastric cancer cells. Inhibition of the Nrf2/GPX4 pathway induces ferroptosis in gastric cancer cells. Compared with the capecitabine group， the 20% BXT group showed a more obvious effect. ConclusionBanxia Xiexintang can induce ferroptosis in gastric cancer cells HGC-27， MKN-45， and AGS by inhibiting the Nrf2/GPX4 pathway.

Objective To explore the role of breast/ovarian cancer susceptibility gene 1 associated protein 1(BAP1)in the occurrence and progression of human malignant glioma and the feasibility of BAP1 as a clinical diagnostic marker for malignant glioma.Methods The differential expression of BAP1 in normal and glioma tissue was analyzed based on the GSE4290 and GSE90598 sub-datasets from the gene expression omnibus(GEO)database.Receiver operating characteristic(ROC)curve analysis was conducted to assess the early diagnostic value of BAP1 for malignant glioma.Primary lesion tissues from 28 nonpaired malignant glioma patients and non-tumor brain tissues removed by internal decompression surgery in 5 patients with traumatic brain injury collected independently were collected,and the expression levels of BAP1 were measured using quantitative real-time polymerase chain reaction(qRT-PCR).Specific small interfering RNAs(siRNAs)targeting BAP1 were transiently transfected into U251 cells to further evaluate their interference efficiency.Flow cytometry was employed to analyze changes in the cell cycle and apoptosis of U251 cells with BAP1 knockdown.Results The results of bioinformatics showed that the expression of BAP1 in malignant glioma tissues was lower than that in normal brain tissues(GSE 4290:1 209±18.49 vs 1 476±53.90,GSE 90598:5.19±0.10 vs 5.65±0.21),and the differences were significant(t=5.115,2.267,all P<0.05).ROC curve showed that BAP1 could efficiently differentiate malignant glioma tissue from normal brain tissue(GSE4290:AUC=0.78,GSE90598:AUC=0.75,all P<0.05).The expression level of BAP1 in primary malignant glioma tissue was lower than that in normal brain tissue(0.27±0.04 vs 1.06±0.07),and the difference was significant(t=10.22,P<0.001).After down-regulating the expression of BAP1 in U251 cells,the proportion of S phase cells increased from 17.59%to 27.21%(siBAP1-1)and 25.79%(siBAP1-2),respectively,and the differences were significant(t=6.576,6.642,all P<0.01).However,the apoptosis levels decreased from 10.17%to 2.70%(siBAP-1)and 3.00%(siBAP-2),respectively,and the differences were significant(t=10.31,9.428,all P<0.01).Conclusion Histone H2A deubiquitinase BAP1 could exert the function of tumor suppressor genes by inhibiting rapid cell cycle progression and promoting apoptosis in malignant glioma,and could serve as a potential clinical diagnostic biomarker for malignant glioma.

Objective To investigate the influencing factors of peripheral infections of knee joint tumor prosthesis as well as the value of serum D-D and TLR2 in predicting the infection risks so as to provide a reference for early diagnosis of tumorous periprosthetic infection(PJI)of knee joint.Methods The patients who were treated and followed up in our department from January 2008 to June 2020 were selected.According to the inclusion and exclusion criteria,136 of the patients were selected.The data including age,gender,BMI,history of diabetes,smoking history,tumor location,stage of malignant tumor,operation time,osteotomy length,intraoperative bleed-ing,and the percentage of neutrophils,leukocytes,serum D-dimer,and serum TLR value 3 days after operation were collected.The risk factors of PJI and the diagnostic value of serum D-dimer and serum TLR were analyzed.Results The incidence of PJI was 11.76%.Postoperative chemotherapy and operation time≥180 min were the risk factors of PJI(P<0.05).The area under curve(AUC)of the combination of two indicators,serum D-dimer and serum TLR2 were 0.917,0.894 and 0.778,respectively.The AUC of TLR2 was lower than that of the combina-tion of two indicators(P<0.05);The sensitivity was 0.975,0.908 and 0.708,respectively,and the specificity was 0.75,0.75,and 0.812,respectively.Conclusion Postoperative chemotherapy and operation time≥180 min are the risk factors of PJI.The combination of D-dimer and TLR2 has good diagnostic value.

Based on UPLC-Q-orbitrap-MS and biological network analysis tools, the mechanism of Xihuang Pill in improving hyperplasia of mammary glands was systematically analyzed. The rat model of hyperplasia of mammary glands was established by intramuscular injection of estradiol benzoate and progesterone. LC-MS tissue metabolomics was used to explore the key metabolites and metabolic pathways of Xihuang Pill in improving hyperplasia of mammary glands in rat. The network analysis of the key metabolites regulated by Xihuang Pill was carried out by integrating biological network analysis tools, focusing on the key metabolic pathways, and exploring the potential targets of Xihuang Pill to improve hyperplasia of mammary glands. Compared with the control group, there were significant differences in the content of 49 differential metabolites in the tissues of the model group (P < 0.05). Xihuang Pills could significantly call back 17 metabolites such as L-alanine, threonine, indole-3-carboxylic aldehyde, lysine, arginine, alanylleucine, glycyltyrosine, γ-glutamyl leucine, vitamin B3, serine leucine, threonine leucine, isoleucine glutamic acid, γ-glutamyl tyrosine, decanoyl-L-carnitine, uric acid, leucylleucine, S-adenosyl-methionine. Further network analysis and literature research on the key metabolites regulated by Xihuang Pills showed that the AGE-RAGE signaling pathway may be one of the important pathways for Xihuang Pills to improve hyperplasia of mammary glands. STAT3, MAPK1, EGFR, CASP3, CASP8, PRKCA and JUN in the AGE-RAGE signaling pathway may be potential targets for Xihuang Pills to improve hyperplasia of mammary glands. The animal experiment operations involved in this paper follow the provisions of the Animal Ethics Committee of Gansu University of Traditional Chinese Medicine and pass the ethical review of animal experiments (approval number: 2022-705).

Objective To discuss the clinical safety,feasibility and efficacy of transcatheter arterial infusion chemotherapy(TAI)combined with lipiodol chemoembolization in the treatment of advanced colorectal cancer(CRC).Methods The clinical data of 37 patients with advanced CRC,who received TAI combined with lipiodol chemoembolization at the First Affiliated Hospital of Zhengzhou University of China between June 2016 and December 2022,were retrospectively analyzed.The clinical efficacy was evaluated,the progression-free survival(PFS)and the serious complications were recorded.Results A total of 55 times of TAI combined with lipiodol chemoembolization procedures were successfully accomplished in the 37 patients.The mean used amount of lipiodol emulsion was 2.9 mL(0.8-10 mL).No serious complications such as bleeding and intestinal perforation occurred.The median follow-up time was 24 months(range of 3-48 months).The postoperative one-month,3-month,6-month and 12-month objective remission rates(ORR)were 67.6%(25/37),67.6%(25/37),64.9%(24/37)and 56.8%(21/37)respectively,and the postoperative one-month,3-month,6-month and 12-month disease control rates(DCR)were 91.9%(34/37),91.9%(34/37),89.2%(33/37)and 81.1%(30/37)respectively.The median PFS was 16 months(range of 2-47 months).As of the last follow-up,22 patients survived and 15 patients died of terminal stage of tumor.Conclusion Preliminary results of this study indicate that TAI combined with lipiodol chemoembolization is clinically safe and effective for advanced CRC,and it provide a new therapeutic method for patients with advanced CRC.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disease caused by abnormal expression of glycosylphosphatidylinositol (GPI) on the cell membrane due to mutations in the phosphatidylinositol glycan class A(PIGA) gene. It is commonly characterized by intravascular hemolysis, repeated thrombosis, and bone marrow failure, as well as multiple systemic involvement symptoms such as renal dysfunction, pulmonary hypertension, swallowing difficulties, chest pain, abdominal pain, and erectile dysfunction. Due to the rarity of PNH and its strong heterogeneity in clinical manifestations, multidisciplinary collaboration is often required for diagnosis and treatment. Peking Union Medical College Hospital, relying on the rare disease diagnosis and treatment platform, has invited multidisciplinary clinical experts to form a unified opinion on the diagnosis and treatment of PNH, and formulated the Expert Consensus of Multidisciplinary Diagnosis and Treatment for Paroxysmal Nocturnal Hemoglobinuria (2024), with the hope of promoting the standardization of PNH diagnosis and treatment.