Myocardial infarction (MI) is the leading cause of cardiovascular disease-related death worldwide. Nonetheless, existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence. Caffeic acid (CA) is a bioactive polyphenolic compound with important anti-inflammatory, anti-bacterial and anti-oxidant functions. Still, its specific role and mechanism in treating cardiovascular disease remain to be further studied. In recent years, a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway is a key factor in the occurrence and development of cardiovascular diseases. In this study, H₂O₂-induced oxidative stress model of H9c2 cells and left anterior descending branch (LAD) conjunctival induced acute myocardial infarction reperfusion (AMI/R) model were used to evaluate the protective effect of CA on the heart. The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe, target fishing, isothermal titration calorimetry (ITC), protein crystallography and surface plasmon resonance (SPR). Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner, further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress. In addition, based on the three-dimensional eutectic structure, it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532, inducing conformation changes in Keap1 protein. We also found that the CA analog chlorogenic acid (GCA) can bind Keap1. In conclusion, this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors.The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT’s multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Objective To evaluate the safety of the low glucoside composites of Epimedii Folium and clarify the pharmacokinetic characteristics of its five low glucosides.Methods Four groups of KM mice were orally administrated of corn oil,1 968,2 625 and 3 500 mg·kg-1 low glucoside composites of Epimedii Folium,respectively.Then,the living conditions,toxic symptoms,and death of the mice were observed for 7 consecutive days.After the mice were dissected,the viscera/body ratio and the viscera/brain ratio were calculated.Besides,the contents of alanine aminotransferase(ALT)and aspartate transaminase(AST)in plasma were determined by ELISA,and the pathological changes of the liver were observed by HE staining.C57BL/6J mice were intravenously or orally administered of baohuoside I,baohuoside II,sagittatoside A,sagittatoside B and sagittatoside C.Then,blood samples were collected at different time points.The plasma concentrations of the five low glucosides were measured by UHPLC-MS/MS.Results When compared with the control group,no significant differences were found in the body mass,viscera/body ratio,viscera/brain ratio,contents of ALT and AST in plasma after oral administration of different doses of low glucoside composites to mice.Moreover,no pathological changes or damages were found in the liver sections.After intravenous injection,the AUC0-t values of baohuoside Ⅰ,baohuoside Ⅱ,sagittatoside A,sagittatoside B and sagittatoside C in mice were 4.82,82.54,276.64,88.77 and 178.02 min·μg·mL-1,respectively.Meanwhile,the t1/2 values were 60.42,115.27,67.63,131.61 and 129.87 min,respectively.After oral administration,the AUC0-t values of the five low glucosides were 31.64,18.59,3.48,2.41 and 2.42 min·μg·mL-1,respectively.The Cmax values were 147.23,86.76,15.58,24.34 and 26.12 ng·mL-1,respectively.The tmax values were 21.00,78.00,78.00,30.00 and 28.00 min,respectively.The bioavailability of baohuosideⅠ,baohuosideⅡ,sagittatoside A sagittatoside B and sagittatoside C were 1.91%,0.51%,0.05%,0.06%and 0.04%,respectively.Conclusion The low glucoside composites of Epimedii Folium has high safety,and no hepatotoxicity were observed at dose of 3 500 mg·kg-1.The 5 low glucosides are quickly absorbed and rapidly eliminated in mice,and all of them have low bioavailability.

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors.The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT’s multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Although olaparib has demonstrated substantial clinical benefits as maintenance therapy in BRCA mutation-carrying women with newly diagnosed advanced ovarian cancer, its effectiveness in patients without BRCA mutations remains poorly investigated. This study aims to provide the first evidence on the efficacy of mono-olaparib maintenance therapy in such context. Using real-world data from 11 high-volume tertiary care centers in China, a retrospective cohort study was conducted to assess the efficacy and safety of olaparib as first-line maintenance therapy in patients with BRCA wild-type ovarian cancer. The primary objective was 1-year progression-free survival rate. Safety was also evaluated. Fifty patients with a median age of 54 years were included, and all of them tested negative for BRCA mutations but positive for homologous recombination deficiency (HRD). The 1-year PFS rate was 75.2% (95% CI, 63.4 to 89.2), and the median PFS was 21.0 months (95% CI, 13.8 to 28.2). All the patients received olaparib at a starting dose of 300 mg twice daily, and none experienced serious adverse events (AEs). Eight (16%) patients had dose adjustment, but none discontinued olaparib treatment due to AEs. We provide the first evidence that mono-olaparib could be a safe and effective maintenance treatment option for patients newly diagnosed with HRD-positive/BRCA wild-type ovarian cancer.
Humans ; Female ; Phthalazines/adverse effects* ; Piperazines/administration & dosage* ; Middle Aged ; Ovarian Neoplasms/genetics* ; Retrospective Studies ; Adult ; Aged ; Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage* ; China ; Maintenance Chemotherapy ; BRCA2 Protein/genetics* ; Antineoplastic Agents/adverse effects* ; Progression-Free Survival ; BRCA1 Protein/genetics*

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors.The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT’s multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Objective:To investigate the clinical and epidemiological characteristics of community-acquired Mycoplasma pneumoniae (Mp) pneumonia in children in Hainan region, as well as the efficacy of low-dose methylprednisolone adjuvant therapy. Methods:Children with community-acquired pneumonia (CAP) in Hainan Women and Children′s Medical Center from October 2021 to September 2022 were enrolled. Sputum or nasopharyngeal swabs were collected and respiratory pathogens were detected by multiplex fluorescence quantitative polymerase chain reaction capillary electrophoresis fragment analysis. The clinical features, epidemiological characteristics, severity of disease and detection of combined pathogens of the children were analyzed. The clinical characteristics and outcomes of children with and without low-dose methylprednisolone (once a day, 1 to 2 mg/kg each time) adjuvant therapy were analyzed. Statistical analysis was performed using the nonparametric rank-sum test.Results:A total of 3 032 children who were hospitalized with CAP underwent testing for respiratory pathogens. The positive detection rate of Mp was 25.46%(772/3 032), and Mp was prevalent throughout the year, with a high detection rate of 47.06% to 64.84% from May to September. Among the children with Mp pneumonia, the age was 5.4(2.9, 7.6) years, 446 cases (57.77%) were detected with other respiratory pathogens, 84.84%(655/772) had fever with a duration of 6(2, 7) days, 75.57% of the children had high fever (the peak temperature was more than 39 ℃), and 98.96%(764/772) had cough. There were 100 cases (12.95%) developed severe Mp pneumonia, mostly in children under five years of age (67.00%(67/100)), 30.00%(30/100) with wheezing, 17.00%(17/100) with pulmonary atelectasis, and 4.00%(4/100) with pleural effusion. Comparison with children who did not use methylprednisolone, children treated with methylprednisolone achieved clinical resolution of fever faster (1.0(0, 1.0) d vs 6.0(4.0, 7.0) d), and the difference was statistically significant ( Z=-15.82, P<0.001). There were nine children with early methylprednisolone treatment and 411 children with delayed methylprednisolone treatment, and there was no significant difference in time to clinical resolution of fever between early and delayed methylprednisolone treatment (0.5(0, 1.0) d vs 1.0(0, 1.0) d; Z=-0.71, P=0.479). Conclusions:Mp is a common pathogen causing CAP in children older than five years in Hainan region, which is mostly accompanied by clinical symptoms of high fever. Severe cases are mostly seen in children younger than five years, with the presence of wheezing, pulmonary atelectasis, pleural effusion. Low-dose methylprednisolone combined with antimicrobial treatment can significantly shorten the clinical fever time in children with Mp. Mp pneumonia is often associated with the detection of various other pathogens, but infection should be distinguished from colonization.

Objective:To investigate the clinical and epidemiological characteristics of community-acquired Mycoplasma pneumoniae (Mp) pneumonia in children in Hainan region, as well as the efficacy of low-dose methylprednisolone adjuvant therapy. Methods:Children with community-acquired pneumonia (CAP) in Hainan Women and Children′s Medical Center from October 2021 to September 2022 were enrolled. Sputum or nasopharyngeal swabs were collected and respiratory pathogens were detected by multiplex fluorescence quantitative polymerase chain reaction capillary electrophoresis fragment analysis. The clinical features, epidemiological characteristics, severity of disease and detection of combined pathogens of the children were analyzed. The clinical characteristics and outcomes of children with and without low-dose methylprednisolone (once a day, 1 to 2 mg/kg each time) adjuvant therapy were analyzed. Statistical analysis was performed using the nonparametric rank-sum test.Results:A total of 3 032 children who were hospitalized with CAP underwent testing for respiratory pathogens. The positive detection rate of Mp was 25.46%(772/3 032), and Mp was prevalent throughout the year, with a high detection rate of 47.06% to 64.84% from May to September. Among the children with Mp pneumonia, the age was 5.4(2.9, 7.6) years, 446 cases (57.77%) were detected with other respiratory pathogens, 84.84%(655/772) had fever with a duration of 6(2, 7) days, 75.57% of the children had high fever (the peak temperature was more than 39 ℃), and 98.96%(764/772) had cough. There were 100 cases (12.95%) developed severe Mp pneumonia, mostly in children under five years of age (67.00%(67/100)), 30.00%(30/100) with wheezing, 17.00%(17/100) with pulmonary atelectasis, and 4.00%(4/100) with pleural effusion. Comparison with children who did not use methylprednisolone, children treated with methylprednisolone achieved clinical resolution of fever faster (1.0(0, 1.0) d vs 6.0(4.0, 7.0) d), and the difference was statistically significant ( Z=-15.82, P<0.001). There were nine children with early methylprednisolone treatment and 411 children with delayed methylprednisolone treatment, and there was no significant difference in time to clinical resolution of fever between early and delayed methylprednisolone treatment (0.5(0, 1.0) d vs 1.0(0, 1.0) d; Z=-0.71, P=0.479). Conclusions:Mp is a common pathogen causing CAP in children older than five years in Hainan region, which is mostly accompanied by clinical symptoms of high fever. Severe cases are mostly seen in children younger than five years, with the presence of wheezing, pulmonary atelectasis, pleural effusion. Low-dose methylprednisolone combined with antimicrobial treatment can significantly shorten the clinical fever time in children with Mp. Mp pneumonia is often associated with the detection of various other pathogens, but infection should be distinguished from colonization.

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH₂-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.

Objective:To explore the relationship between hematocrit, early fluid therapy, and clinical outcomes in patients with septic shock, and to provide evidence for fluid resuscitation therapy and prognosis assessment in these patients.Methods:The clinical information of patients with septic shock who were diagnosed and treated in the Emergency Intensive Care Unit (EICU) of the First Affiliated Hospital of Wenzhou Medical University from January 1, 2018 to December 31, 2020 were collected. Taking the survival or death of patients 28 days after admission as the end point of clinical research, the patients were divided into the survival and death groups. After analyzing the basic data of the two groups, the univariate and multivariate COX regression analyses were used to analyze the evaluation value of Δ Hematocrit (HCT) d2-d1 and ΔHCT d3-d1 on the prognosis of patients with septic shock. At the same time, the Kaplan-Meier survival curve was used to analyze the overall survival rate of patients with septic shock, and the smooth curve fitting graph was used to verify its relationship with net fluid intake and death. Results:There were 241 cases in the survival group and 67 cases in the death group. Univariate COX analysis showed statistically significant differences between the survival and death groups in acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) ( P=0.0006), red cell volume distribution width (RDW) ( P=0.0043), age ( P=0.0184), ΔHCT d2-d1 ( P=0.0136), ΔHCT d3-d1 ( P=0.0204), and white blood cell (WBC) ( P=0.0444). Multivariate COX analysis showed that ΔHCT d2-d1 ( P=0.0115) and ΔHCT d3-d1 ( P=0.0029) were independent risk factors for death in EICU patients with septic shock. ΔHCT d2-d1 and ΔHCT d3-d1 were divided into three groups according to the three-digit method. The Kaplan-Meier survival curve showed no significant difference among the three groups in the overall survival rate related to ΔHCT d2-d1 ( P=0.16), but there was a statistically significant difference in the overall survival rate among the three groups related to ΔHCT d3-d1 ( P=0.025). The smooth fitting curve of ΔHCT d3-d1, net fluid intake, and prognosis showed that ΔHCT d3-d1 was negatively correlated with net fluid intake, and the middle ΔHCT d3-d1 group had the best prognosis. Conclusions:The value of ΔHCT d3-d1 is related to the net fluid intake of patients with septic shock. An appropriate decrease in HCT on the third day can improve the prognosis of patients with septic shock. The dynamic changes of hematocrit can provide a certain basis for fluid resuscitation and prognosis evaluation in patients with septic shock.