Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

Objective:To observe and analyze the correlation between ectopic foveal inner layer (EIFL) and the EIFL-based idiopathic epiretinal membrane (ERM) staging system and the anatomic and functional prognosis of ERM eyes post pars plana vitrectomy (PPV).Methods:A retrospective study. From January 1, 2020 to October 30, 2023, 345 eyes of 330 patients diagnosed with idiopathic ERM in Department of Ophthalmology of Peking University People's Hospital and treated with standard transciliary flat three-channel 25G PPV combined with ERM and internal limiting membrane exfoliation were included in the study. Among them, 96 were males (111 eyes) and 234 were females (234 eyes). The mean age was (66.8±7.7) years. All study eyes received standard three-port 25G PPV combined with ERM and internal limiting membrane peeling. All study eyes underwent best corrected visual acuity (BCVA) and optical coherence tomography (OCT) examinations. BCVA was performed using a standard logarithmic visual acuity chart and converted to logarithm of the minimum angle of resolution visual acuity for statistical analysis. EIFL thickness and central foveal thickness (CFT) on OCT were measured. ERM eyes were grouped into stage Ⅰ, Ⅱ, Ⅲ and Ⅳ according to ERM staging scheme based on EIFL; disorganization of the retinal inner layers (DRIL) of study eyes were assessed and grouped into no, mild and severe groups. The correlation between ERM staging as well as EIFL thickness and the anatomical and functional prognosis 6 months post-PPV were analyzed.Results:Among 345 study eyes, 12, 87, 174 and 72 eyes were stage Ⅰ-Ⅳ ERM respectively, 63 with no DRIL, 216 with mild DRIL and 66 with severe DRIL. Among the 153 eyes with macular edema, the edema subsided in 66 eyes (43.1%, 66/153) 6 months after the operation. Eighty-seven eyes (56.9%, 87/153) did not regress. The edema subsided 6 months after the operation was not significantly correlated with the ERM stage before the operation ( χ2=3.331, R=?0.145, P=0.304) or the degree of DRIL ( χ2=0.655, R=?0.108, P=0.445). The results of the correlation analysis showed that logMAR BCVA 6 months after the surgery was positively correlated with the degree of DRIL before the surgery ( Tau-b=0.236), ERM stage ( Tau-b=0.194), CFT ( r=0.383), and EIFL thickness ( r=0.317) ( P<0.05). There was no significant correlation with the thickness of the outer nuclear layer before the operation ( r=0.004, P>0.05). Preoperative ERM stage ( Tau-b=0.303, P<0.001) and DRIL severity ( Tau-b= 0.238, P=0.001) were positively correlated with CFT at 6 months after surgery. Conclusion:The ERM stage and EIFL thickness before the operation are positively correlated with logMAR BCVA and CFT 6 months after the operation.

BACKGROUND:Recent studies have found that Nrf2/ARE signaling pathway activators have the characteristics of low toxicity and control,and have a protective effect against radiation tissue damage.OBJECTIVE:To investigate whether nitrooleic acid can protect submandibular gland epithelial cells from radiation injury by regulating the Nrf2/ARE signaling pathway.METHODS:Rat submandibular gland epithelial cells were cultured in vitro and CCK-8 assay was used to screen the optimal concentration and time of nitrooleic acid administration.Submandibular gland epithelial cells were divided into non-radiation group,radiation control group,nitrooleic acid group,nitrooleic acid+ML385(Nrf2/ARE signaling pathway specific inhibitor)group,and ML385 group.Submandibular gland cells were pretreated with nitrooleic acid and ML385 for 24 hous according to the experimental groups,and then irradiated with 5 Gy radiation to establish the models.At 48 hours after irradiation,CCK-8 assay was used to detect the cell proliferation rate.Real-time quantitative PCR was used to detect the expression of Nrf2,HO-1,and NQO1 mRNA in the cells.Real-time quantitative PCR and enzyme-linked immunosorbent assay were used to detect the cell secretion function and the expression of inflammatory factors.DCFH-DA fluorescent probe kit was used to detect the level of intracellular reactive oxygen species.RESULTS AND CONCLUSION:(1)Compared with the radiation control group,the proliferation rate of submandibular gland epithelial cells and the expression levels of secretion function related factors aquaporin 5 and α-amylase in the nitrooleic acid group of rats increased(P＜0.05),and the expression levels of Nrf2,HO-1,and NQO1 mRNA increased(P＜0.05),while the expression levels of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-αdecreased(P＜0.05),and reactive oxygen species generation reduced(P＜0.01).(2)Compared with the nitrooleic acid group,the addition of nitrooleic acid and ML385 group resulted in a decrease in cell proliferation rate and expression levels of secretion function related factors aquaporin 5 and α-amylase(P＜0.05),and mRNA expressions of Nrf2,HO-1,and NQO1 were all decreased(P＜0.05),while the expression levels of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α increased(P＜0.05),and generation of reactive oxygen species increased(P＜0.05).(3)Results indicated that in the radiation environment,nitrooleic acid has a certain protective effect on the proliferation ability and secretion function of rat submandibular gland epithelial cells,reduces the expression of inflammatory factors,lowers intracellular reactive oxygen species levels,and alleviates the damage of rat submandibular gland epithelial cells caused by radiation.This function may be related to the activation of Nrf2/ARE signaling pathway.

Objective To study the application of autologous natural killer(NK)cells in the treatment of advanced renal cell carcinoma and the changes of immune function and tumor markers in patients.Methods 61 patients with advanced renal cell carcinoma admitted to Gansu Wuwei Tumour Hospital from March 2023 to April 2024 were divided into targeting group(31 cases,given supportive treatment combined with sunitinib malate capsules)and cell group(30 cases,autologous NK cells combined with targeting group)according to the patient's willingness to treat combined with propensity score matching.6 weeks was a treatment cycle,and all patients were treated for 4 cycles.The clinical efficacy of the two groups after 4 cycles of treatment and the occurrence of adverse reactions during treatment were statistically analyzed.The levels of serum cytokines,tumor markers,lymphocyte function and immune function were compared between the two groups before and after 4 cycles of treatment.Results After 4 cycles of treatment,the objective remission rate and disease control rate in the cell group were higher than those in the targeting group(P<0.05).After 4 cycles of treatment,the levels of serum hypoxia-inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF),platelet-derived growth factor(PDGF),carcinoembryonic antigen,carbohydrate antigen 125,carbohydrate antigen 199 and alpha-fetoprotein in the two groups were lower than those before treatment,and those in the cell group were lower than those in the targeting group(P<0.012 5).After 4 cycles of treatment,the levels of serum interleukin-2,interleukin-6,tumor necrosis factor-β,interferon-γ,peripheral blood CD3+,CD4+,NK cells and CD4+/CD8+in the two groups were higher than those before treatment.The levels of serum interleukin-2,tumor necrosis factor-β,interferon-γ,peripheral blood CD3+and NK cells in the cell group were higher than those in the targeting group(P<0.012 5).The level of CD8+in peripheral blood was lower than that before treatment(P<0.012 5),but there was no significant difference between the two groups(P>0.012 5).During the treatment,there was no significant difference in the incidence of diarrhea,nausea and vomiting,alopecia,liver function damage,decreased platelet level and decreased neutrophil level between the cell group and the targeting group(P>0.05).Conclusion The treatment of advanced renal cell carcinoma with autologous NK cells could improve the level of serum cytokines,reduce the level of tumor markers,regulate the function of lymphocytes and immune function,and had a good therapeutic effect.At the same time,it would not increase the incidence of adverse reactions,and the safety was good.

BACKGROUND:Recent studies have found that Nrf2/ARE signaling pathway activators have the characteristics of low toxicity and control,and have a protective effect against radiation tissue damage.OBJECTIVE:To investigate whether nitrooleic acid can protect submandibular gland epithelial cells from radiation injury by regulating the Nrf2/ARE signaling pathway.METHODS:Rat submandibular gland epithelial cells were cultured in vitro and CCK-8 assay was used to screen the optimal concentration and time of nitrooleic acid administration.Submandibular gland epithelial cells were divided into non-radiation group,radiation control group,nitrooleic acid group,nitrooleic acid+ML385(Nrf2/ARE signaling pathway specific inhibitor)group,and ML385 group.Submandibular gland cells were pretreated with nitrooleic acid and ML385 for 24 hous according to the experimental groups,and then irradiated with 5 Gy radiation to establish the models.At 48 hours after irradiation,CCK-8 assay was used to detect the cell proliferation rate.Real-time quantitative PCR was used to detect the expression of Nrf2,HO-1,and NQO1 mRNA in the cells.Real-time quantitative PCR and enzyme-linked immunosorbent assay were used to detect the cell secretion function and the expression of inflammatory factors.DCFH-DA fluorescent probe kit was used to detect the level of intracellular reactive oxygen species.RESULTS AND CONCLUSION:(1)Compared with the radiation control group,the proliferation rate of submandibular gland epithelial cells and the expression levels of secretion function related factors aquaporin 5 and α-amylase in the nitrooleic acid group of rats increased(P＜0.05),and the expression levels of Nrf2,HO-1,and NQO1 mRNA increased(P＜0.05),while the expression levels of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-αdecreased(P＜0.05),and reactive oxygen species generation reduced(P＜0.01).(2)Compared with the nitrooleic acid group,the addition of nitrooleic acid and ML385 group resulted in a decrease in cell proliferation rate and expression levels of secretion function related factors aquaporin 5 and α-amylase(P＜0.05),and mRNA expressions of Nrf2,HO-1,and NQO1 were all decreased(P＜0.05),while the expression levels of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α increased(P＜0.05),and generation of reactive oxygen species increased(P＜0.05).(3)Results indicated that in the radiation environment,nitrooleic acid has a certain protective effect on the proliferation ability and secretion function of rat submandibular gland epithelial cells,reduces the expression of inflammatory factors,lowers intracellular reactive oxygen species levels,and alleviates the damage of rat submandibular gland epithelial cells caused by radiation.This function may be related to the activation of Nrf2/ARE signaling pathway.

Objective To study the application of autologous natural killer(NK)cells in the treatment of advanced renal cell carcinoma and the changes of immune function and tumor markers in patients.Methods 61 patients with advanced renal cell carcinoma admitted to Gansu Wuwei Tumour Hospital from March 2023 to April 2024 were divided into targeting group(31 cases,given supportive treatment combined with sunitinib malate capsules)and cell group(30 cases,autologous NK cells combined with targeting group)according to the patient's willingness to treat combined with propensity score matching.6 weeks was a treatment cycle,and all patients were treated for 4 cycles.The clinical efficacy of the two groups after 4 cycles of treatment and the occurrence of adverse reactions during treatment were statistically analyzed.The levels of serum cytokines,tumor markers,lymphocyte function and immune function were compared between the two groups before and after 4 cycles of treatment.Results After 4 cycles of treatment,the objective remission rate and disease control rate in the cell group were higher than those in the targeting group(P<0.05).After 4 cycles of treatment,the levels of serum hypoxia-inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF),platelet-derived growth factor(PDGF),carcinoembryonic antigen,carbohydrate antigen 125,carbohydrate antigen 199 and alpha-fetoprotein in the two groups were lower than those before treatment,and those in the cell group were lower than those in the targeting group(P<0.012 5).After 4 cycles of treatment,the levels of serum interleukin-2,interleukin-6,tumor necrosis factor-β,interferon-γ,peripheral blood CD3+,CD4+,NK cells and CD4+/CD8+in the two groups were higher than those before treatment.The levels of serum interleukin-2,tumor necrosis factor-β,interferon-γ,peripheral blood CD3+and NK cells in the cell group were higher than those in the targeting group(P<0.012 5).The level of CD8+in peripheral blood was lower than that before treatment(P<0.012 5),but there was no significant difference between the two groups(P>0.012 5).During the treatment,there was no significant difference in the incidence of diarrhea,nausea and vomiting,alopecia,liver function damage,decreased platelet level and decreased neutrophil level between the cell group and the targeting group(P>0.05).Conclusion The treatment of advanced renal cell carcinoma with autologous NK cells could improve the level of serum cytokines,reduce the level of tumor markers,regulate the function of lymphocytes and immune function,and had a good therapeutic effect.At the same time,it would not increase the incidence of adverse reactions,and the safety was good.

Objective:To observe and analyze the correlation between ectopic foveal inner layer (EIFL) and the EIFL-based idiopathic epiretinal membrane (ERM) staging system and the anatomic and functional prognosis of ERM eyes post pars plana vitrectomy (PPV).Methods:A retrospective study. From January 1, 2020 to October 30, 2023, 345 eyes of 330 patients diagnosed with idiopathic ERM in Department of Ophthalmology of Peking University People's Hospital and treated with standard transciliary flat three-channel 25G PPV combined with ERM and internal limiting membrane exfoliation were included in the study. Among them, 96 were males (111 eyes) and 234 were females (234 eyes). The mean age was (66.8±7.7) years. All study eyes received standard three-port 25G PPV combined with ERM and internal limiting membrane peeling. All study eyes underwent best corrected visual acuity (BCVA) and optical coherence tomography (OCT) examinations. BCVA was performed using a standard logarithmic visual acuity chart and converted to logarithm of the minimum angle of resolution visual acuity for statistical analysis. EIFL thickness and central foveal thickness (CFT) on OCT were measured. ERM eyes were grouped into stage Ⅰ, Ⅱ, Ⅲ and Ⅳ according to ERM staging scheme based on EIFL; disorganization of the retinal inner layers (DRIL) of study eyes were assessed and grouped into no, mild and severe groups. The correlation between ERM staging as well as EIFL thickness and the anatomical and functional prognosis 6 months post-PPV were analyzed.Results:Among 345 study eyes, 12, 87, 174 and 72 eyes were stage Ⅰ-Ⅳ ERM respectively, 63 with no DRIL, 216 with mild DRIL and 66 with severe DRIL. Among the 153 eyes with macular edema, the edema subsided in 66 eyes (43.1%, 66/153) 6 months after the operation. Eighty-seven eyes (56.9%, 87/153) did not regress. The edema subsided 6 months after the operation was not significantly correlated with the ERM stage before the operation ( χ2=3.331, R=?0.145, P=0.304) or the degree of DRIL ( χ2=0.655, R=?0.108, P=0.445). The results of the correlation analysis showed that logMAR BCVA 6 months after the surgery was positively correlated with the degree of DRIL before the surgery ( Tau-b=0.236), ERM stage ( Tau-b=0.194), CFT ( r=0.383), and EIFL thickness ( r=0.317) ( P<0.05). There was no significant correlation with the thickness of the outer nuclear layer before the operation ( r=0.004, P>0.05). Preoperative ERM stage ( Tau-b=0.303, P<0.001) and DRIL severity ( Tau-b= 0.238, P=0.001) were positively correlated with CFT at 6 months after surgery. Conclusion:The ERM stage and EIFL thickness before the operation are positively correlated with logMAR BCVA and CFT 6 months after the operation.

BACKGROUND:It has been demonstrated that osteoclast activation plays an important role in skeletal system-related diseases.The mechanism of regulation of osteoclast activation by extracellular vesicles carrying non-coding RNA has not been fully elucidated. OBJECTIVE:To review and summarize relevant literature in and outside China,and to review the regulation of osteoclast activation by different non-coding RNAs in extracellular vesicles in different diseases,so as to provide a certain direction for subsequent research. METHODS:"Non-coding RNA,miRNA,lncRNA,circRNA,snoRNA,osteoclasts,extracellular vesicles,exosome,microparticle,apoptotic bodies"were used as search terms to search the databases of CNKI,WanFang,and VIP."Extracellular vesicles,exosome,microparticle,apoptotic bodies,non-coding RNA,miRNA,lncRNA,circRNA,snoRNA,osteoclast"were used as search terms to search PubMed.Finally,71 articles were included. RESULTS AND CONCLUSION:(1)The activation of osteoclasts is affected by many factors,among which the specific mechanism of non-coding RNA regulating osteoclast activation is not clear.(2)Extracellular vesicles can be secreted by osteoblasts,bone marrow mesenchymal stem cells,tumor cells and other cells.As a carrier of intercellular communication,extracellular vesicles can carry non-coding RNA to regulate osteoclast activation.(3)In the current studies on the regulation of osteoclast activation by extracellular vesicles carrying non-coding RNA,most of the diseases are osteoporosis,followed by tumor bone metastasis,and most types of non-coding RNA are miRNA.(4)There are relatively few studies on the regulation of extracellular vesicles carrying lncRNA and circRNA and snoRNA on osteoclast activation,and the regulatory mechanism is mainly ceRNA mechanism.(5)In conclusion,an in-depth study of the regulatory mechanism of extracellular vesicles carrying non-coding RNA on osteoclast activation is helpful to find key targets for the treatment of skeletal system-related diseases.

Objective To explore the relationship between postoperative restenosis and vascular endothelial function in patients with lower extremity arterial disease(LEAD).Methods A retrospective analysis was performed on 133 patients with diabetic lower extremity arteriopathy who had successfully undergone interventional therapy in our hospital,and the patients were followed up for one year,and the patients were grouped according to whether restenosis occurred,with 25 cases in the restenosis group and 108 cases in the non-stenosis group.The patient's vascular endothelial function index,inflammatory factor level,blood lipid four items and hemoglobin A1c(HbAlc)were detected,and peripheral blood cells of patients in the stenosis group and non-stenosis group were isolated for transcriptome sequencing.Multivariate unconditional logistic regression analysis was used to screen for independent risk factors for vascular endothelial function in postoperative restenosis.Results Serum endothelin-1(ET-1),von Willebrand factor(vWF),thromboxane B2(TXB2),vascular cell adhesion protein 1(VCAM-1),and nitric oxide(NO)were significantly higher in the stenosis group than in the non-stenosis group,while endothelial nitric oxide synthase(eNOS)and vascular endothelial growth factor(VEGF)were significantly lower than those in the non-stenosis group(P<0.01).There was no significant difference in blood lipids between the two groups(P>0.05).The HbAlc of the stenosis group was significantly higher than that of the non-stenosis group(P<0.01).The inflammatory factors in the stenosis group were significantly higher than those in the non-stenosis group(P<0.05).Transcriptome sequencing analysis results are consistent with test results.Multivariate Logistic regression analysis showed that TNF-α,IL-6,ET-1,and vWF were independent risk factors for LEAD vascular restenosis(P<0.05).Conclusion Vascular endothelial function indexes(ET-1,vWF)and inflammatory factors(TNF-α,IL-6)are independent risk factors for restenosis after interventional surgery.