Thirteen novel diterpenoids, comprising seven tiglianes (walliglianes G-M, 1-7), four rhamnofolanes (wallinofolanes A-D, 8-11), and two daphnanes (wallaphnanes A and B, 12 and 13), together with two known rhamnofolane diterpenoids (euphorwallside H and euphorwallside I, 14 and 15), were isolated and characterized from Euphorbia wallichii(E. wallichii). The chemical structures of these compounds were elucidated through nuclear magnetic resonance (NMR), mass spectrometry (MS), and quantum chemical calculations. Compounds 9 and 11 demonstrated protective effects against H₂O₂-induced BV-2 microglial cell damage. Molecular docking analyses indicated that compound 9 exhibited binding affinity to the anti-oxidant-related targets HMGCR, GSTP1, and SHBG.
Euphorbia/chemistry* ; Antioxidants/isolation & purification* ; Diterpenes/isolation & purification* ; Molecular Structure ; Mice ; Molecular Docking Simulation ; Animals ; Hydrogen Peroxide/toxicity* ; Cell Line ; Microglia/drug effects*

Objective To explore the mechanism by which electroacupuncture improves ocular surface inflammation in dry eye mice.Methods 30 SPF-grade healthy male ICR mice were randomly divided into a blank group,a model group,a sham electroacupuncture group,a western medicine group and an electroacupuncture group,with 6 mice in each group.Mice in the blank group and other four groups were subcutaneously injected 200 μL of sterile physiological saline and 200 μL of scopolamine hydrobromide(0.5 mg dissolved in 0.2 mL of sterile physiological saline)at 8:00,11:00,14:00,and 17:00 every day for 35 consecutive days,respectively.From the 22nd day,mice in the sham electroacupunc-ture group were given blunt scalp acupuncture intervention at bilateral Jingming and Taiyang points,without subcutaneous penetration.In the western medicine group,fluorometholone eye drops were applied to both eyes of the mice at 8:00,13:00,and 18:00 daily,with 1 drop each time.Mice in the electroacupuncture group were given electroacupuncture in-tervention,with the same acupoint location and acupuncture time as the sham electroacupuncture group.The electroacu-puncture frequency was 2 Hz/20 Hz,the waves were sparse-dense and the intensity was 1 mA,once a day for 15 min.All groups were intervened for 14 days.The corneal fluorescein(FL)staining scores of mice in each group were detected be-fore modeling,after modeling,and after intervention.The corneal tissue morphology was observed under a light micro-scope.Immunohistochemistry staining and quantitative reverse transcription polymerase chain reaction(qRT-PCR)were used to detect the protein and mRNA expression of high mobility group box 1(HMGB1)and receptor for advanced glyca-tion end products(RAGE)in the cornea,respectively.Results The FL scores of mice in model,sham electroacupunc-ture,western medicine,and electroacupuncture groups all significantly increased after modeling and intervention,com-pared with those before modeling(all P＜0.01).The FL scores of mice in electroacupuncture and western medicine groups significantly decreased after intervention,compared with those after modeling(both P＜0.01).Compared with the model group,electroacupuncture and western medicine groups showed a significant drop in FL score after intervention(both P＜0.01).HE staining showed that after intervention,mice in electroacupuncture and western medicine groups had a basically normal number of corneal epithelial layers,no obvious shedding of epithelial cells,and neatly arranged and slightly swollen collagen fibers in the stromal layer.The relative protein expression levels of HMGB1 and RAGE in the corneal tissue of both model and sham electroacupuncture groups were significantly higher than those of the blank group(allP＜0.01).The rela-tive protein expression levels of HMGB1 and RAGE in the corneal tissue of both electroacupuncture and western medicine groups were significantly lower than those of the model group(all P＜0.01).The relative mRNA expression levels of HMGB1 and RAGE in the corneal tissue of both model and sham electroacupuncture groups were significantly higher than those of the blank group(all P＜0.01).The relative mRNA expression levels of HMGB1 and RAGE in the corneal tissue of both electroacupuncture and western medicine groups were significantly lower than those of the model group(all P＜0.01).Conclusion Electroacupuncture mitigates corneal epithelial injury,reduces the expression of HMGB1 in the cor-neal tissue,inhibits the binding of HMGB1 and RAGE,and ultimately alleviates ocular surface inflammation responses of dry eye mice.

Objective:To Evaluate the potential causal relationship between the levels of 179 lipids in peripheral blood and the risk of different subtypes of lung cancer by Mendelian randomization analysis.Methods:A two-sample Mendelian randomization analysis was performed using data from the Genome-Wide Association Study(GWAS),and sensitivity analysis was performed to verify the reliability of the results.Single nucleotide polymorphisms(SNPs)were used as instrumental variables,and GWAS data for different subtypes of lung cancer were used as outcome variables.We analyze potential causal associations between the levels of 179 lipids and the risk of different subtypes of lung cancer.Results:The causal relationship between phosphatidylcholine and lung adenocarcinoma was established as a protective factor,and Sphingomyelin and Triacylglycerol have been identified as being linked to lung adenocarcinoma and function as risk factors.Phosphatidylcholine were found to have a causal association with lung squamous cell carcinoma serving as a protective factor,and Phosphatidylethanolamine and Sphingomyelin were identified as risk factors for lung squamous cell carcinoma.However,the effects of different subtypes of Phosphatidylcholine on lung adenocarcinoma and lung squamous cell carcinoma were different.The study did not find evidence that lipids can influence small cell lung carcinoma.Conclusion:This study provides evidence of a causal relationship between lipids level features and different subtypes of lung cancer.

Objective:To explore the efficacy and factors affecting the treatment of gastric cancer liver metastasis (GCLM) with immune checkpoint inhibitors (ICI).Methods:This is a retrospective cohort study. Clinical and pathological data of 588 patients with GCLM treated at the Department of General Surgery, First Medical Center, People′s Liberation Army General Hospital, from January 2018 to December 2022 were retrospectively collected. There were 491 males and 97 females, aged ( M(IQR)) 60(14) years (range: 18 to 86 years). Patients were divided into an ICI treatment group ( n=142) and a non-ICI treatment group ( n=446) based on whether they received ICI therapy. Clinical and pathological data between the two groups were compared using the χ2 test or Mann-Whitney U test. Propensity score matching (PSM) was performed with cT stage, cN stage, surgical treatment, targeted therapy, and biomarkers as covariates, using a 1∶1 nearest neighbor matching method with a caliper value of 0.2. Univariate and multivariate analyses were conducted using Cox proportional hazards regression models, with relevant variables selected through forward stepwise regression. Survival curves were plotted using the Kaplan-Meier method, and group differences were compared using the Log-rank test. Subgroup analysis was conducted to identify potential beneficiary populations for ICI through forest plots. Results:After PSM, 114 patients were included in each group, and there were no statistically significant differences in the baseline data between the two groups (all P>0.05). The results of Cox multivariate analysis after PSM showed that cN2-3 stage ( HR=1.348, 95% CI: 1.091 to 1.665, P=0.006) and peritoneal metastasis ( HR=1.877, 95% CI:1.360 to 2.590, P<0.01) were independent risk factors for survival in GCLM patients; radical surgery ( HR=0.391, 95% CI: 0.305 to 0.501, P<0.01), immunotherapy ( HR=0.630, 95% CI: 0.503 to 0.788, P<0.01), and deficient DNA mismatch repair (dMMR) or combined positive score (CPS)≥5 ( HR=0.454, 95% CI: 0.320 to 0.644, P<0.01) were independent protective factors for survival in GCLM patients. After PSM, the overall survival was 12.4 (13.0) months in the non-immunotherapy group and 17.6 (17.8) months in the immunotherapy group (Log-rank test: P=0.029). Subgroup analysis showed that female patients, those with primary tumors located in the upper stomach, cN2-3 stage, one liver metastasis, synchronous liver metastasis, receiving targeted therapy, and those with dMMR or CPS≥5 were more likely to benefit from ICI therapy (all P<0.05). Conclusions:ICI prolongs overall survival in GCLM patients. Female patients, those with primary tumors located in the upper stomach, cN2-3 stage, one liver metastasis, synchronous liver metastasis, receiving targeted therapy, and those with dMMR or CPS≥5 are more likely to benefit from ICI therapy.

Objective To investigate the mediating role of anxiety and depression in social sup-port and burnout among primary caregivers of stroke patients.Methods A convenience sampling method was employed to select 506 primary caregivers of stroke patients as research subjects.The Gen-eral Information Questionnaire,Caregiver Burnout Inventory for Stroke Patients,Multidimensional Scale of Perceived Social Support,and Hospital Anxiety and Depression Scale were used for data col-lection.Results The total scores for caregiver burnout,social support,anxiety,and depression a-mong primarycaregivers of stroke patients were(72.83±14.32),(47.79±7.74),(10.49±3.00),and(10.45±3.06),respectively.Correlation analysis revealed a negative correlation between caregiver burnout and social support(r=-0.245,P＜0.001),and positive correlations with anxiety and depression(r=0.178,0.216,P＜0.001).Anxiety and depression partially media-ted the relationship between social support and caregiver burnout,accounting for 7.9％and 10.7％of the total effect,respectively.Conclusion Social support,anxiety,depression,and burnout are closely interrelated.Social support can directly or indirectly influence the occurrence of burnoutthrough anxiety and depression.Medical staff should pay attention to the anxiety and depression status of primary caregivers of stroke patients and enhance social support levels to reduce the incidence of burnout by alleviating anxiety and depression.

Objective:To investigate the effect of Qinggan Bupi Jiangtang Decoction combined with acupuncture on glucose and lipid metabolism and cytokines in patients with overweight/obese T2DM.Methods:Randomized controlled trial. A total of 104 patient with overweight/obese T2DM who were admitted to the Shanghai Municipal Hospital of Traditional Chinese Medicine of Shanghai University of Traditional Chinese Medicine from September 2022 to March 2023 were selected as the research subjects. They were randomly divided into the control group (52 cases) and the combination group (52 cases). The control group was given conventional symptomatic treatment and treated with acupuncture. On this basis, the combination group was treated with Qinggan Bupi Jiangtang Decoction. The two groups were compared in terms of efficacy, TCM syndrome scores, glucose metabolism indicators, islet function indicators, lipid metabolism indicators, cytokines, and blood glucose control. Results:The total effective rate was 90.38% (47/52) in the combined group and 73.08% (38/52) in the control group, and the difference between the two groups was statistically significant ( χ2=5.22, P=0.022). After treatment, the TCM syndrome score (13.21±1.48 vs. 18.54±2.01, t=15.40) of the combination group was lower than that of the control group ( P<0.001). After treatment, the combination group FPG [(6.05 ± 1.01) mmol/L vs. (7.26 ± 1.13) mmol/L, t=5.73], 2 hPG [(8.23 ± 1.12) mmol/L vs. (10.41 ± 1.26) mmol/L, t=9.54], HbAlc [(5.84 ± 0.84) % vs. (6.31 ± 0.93) %, t=2.84] and HOMA-IR (2.57 ± 0.26 vs. 2.86 ± 0.30, t=3.75) were lower than those in the control group ( P<0.05), and HOMA-β (61.34 ± 6.75 vs. 56.69 ± 5.72, t=5.87) was higher than that of the control group ( P<0.05). After treatment, the combination group TC, TG and LDL-C were lower than those in the control group ( t values were 10.25, 5.35, 3.51, respectively, P<0.01), HDL-C was higher than that of the control group ( t=11.59, P<0.01). After treatment, the combination group CTRP12 [(296.05 ± 30.11) ng/L vs. (280.23 ± 28.44) ng/L, t=2.76], FGF-21 [(184.12 ± 19.05) μg/L vs. (170.04 ± 17.03) μg/L, t=2.77], Nesfatin1 [(0.92 ± 0.10) μg/L vs. (0.77±0.08) μg/L, t=5.99] and lipidin levels [(4.89±0.51) mg/L vs. (4.12±0.48) mg/L, t=8.58] were higher than those in the control group ( P<0.01). The combined group composite endpoint achievement rate was 53.85% (28/52), the 12-week HbA1c achievement rate was 80.77% (42/52), and the rate of no weight increase was 84.62% (44/52). The control group's composite endpoint achievement rate was 34.62% (18/52), the 12-week HbA1c achievement rate was 61.54% (32/52), and the rate of no weight increase was 67.31% (35/52). The differences between the two groups were statistically significant ( χ2 values were 3.90, 4.69, 4.27, respectively, and the P values were 0.048, 0.030, 0.039, respectively). The adverse reactions of the two groups were mainly mild nausea, skin rash and pruritus, the incidence of which was 15.38% (8/52) in the combination group and 9.62% (5/52) in the control group, and there was no significant difference between the two groups ( χ2=0.79, P=0.374). Conclusion:The therapeutic effect of Qinggan Bupi Jiangtang Decoction combined with acupuncture on overweight/obese T2DM patients is relatively clear, and it can regulate the glucose and lipid metabolism and cytokines of patients.

Objective To observe the clinical efficacy of Dan Qi Yishen Prescription in treating diabetic nephropathy(DN)and explore its renal protective mechanism.Methods A total of 150 patients with DN of qi-yin deficiency complicated with blood stasis syndrome who admitted to Sanya Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine from October 2021 to April 2023 were divided into a control group and an observation group according to the random number table method,with 75 patients in each group.Both groups were given conventional therapies such as dietary treatment,blood glucose control,blood pressure control,lipid-lowering treatment and treatment of complications.Additionally,the control group was given intravenous injection of reduced glutathione,while the observation group was given oral use of the decoction of Dan Qi Yishen Prescription and ionic introduction of Dan Qi Yishen Prescription in renal region.Thirty days constituted one course of treatment,and both groups were treated for three courses.Before and after treatment,the scores of traditional Chinese medicine(TCM)syndrome,and the levels of renal function indicators,renal hemodynamic indicators,coagulation and fibrinolysis indicators,and vascular endothelial function indicators in the two groups were observed.Results(1)After treatment,the scores of TCM symptoms such as fatigue and weakness,palpitations and shortness of breath,dizziness and tinnitus,spontaneous sweating and night sweating,restlessness and insomnia,and thirst with preference for drinks in the two groups were decreased compared with those before treatment(P<0.01),and the decrease in the observation group was significantly superior to that in the control group(P<0.01).(2)After treatment,the levels of renal function indicators such as blood urea nitrogen(BUN),serum creatinine(SCr),collagen Ⅳ(CⅣ),and plasma laminin(LN)of patients in the two groups were improved compared with those before treatment(P<0.01),and the improvement in the observation group was significantly superior to that in the control group(P<0.01).(3)After treatment,the levels of renal hemodynamic indicators such as systolic maximum blood flow velocity(Vsmax)and diastolic minimum blood flow velocity(Vdmin)of the main renal artery(MRA)and interlobar artery(IRA)in the two groups were increased compared with those before treatment(P<0.05 or P<0.01),while the resistance index(RI)and pulsatility index(PI)of MRA and RI of IRA in the two group as well as PI of IRA in the observation group were decreased compared with those before treatment(P<0.05 or P<0.01).The increase of Vsmax and Vdmin of MRA and IRA as well as the decrease of RI and PI of MRA and IRA in the observation group was significantly superior to that in the control group(P<0.05 or P<0.01).(4)After treatment,the levels of coagulation and fibrinolysis indicators such as prothrombin time(PT),activated partial thromboplastin time(APTT),D-dimer(D-D),and fibrinogen(FIB)in the two groups were improved compared with those before treatment(P<0.01),and the improvement in the observation group was significantly superior to that in the control group(P<0.01).(5)The analysis of vascular endothelial function indicators showed that after treatment,the serum vasohibin 1(VASH-1)level in the two groups was increased compared with that before treatment(P<0.01),and the serum vascular endothelial growth factor(VEGF)and endothelin 1(ET-1)levels were decreased compared with those before treatment(P<0.01),and the increase of serum VASH-1 level as well as the decrease of serum VEGF and ET-1 levels in the observation group was significantly superior to that in the control group(P<0.01).Conclusion Dan Qi Yishen Prescription exerts good clinical efficacy in treating patients with DN of qi-yin deficiency complicated with blood stasis syndrome,and it has protective effect on renal function probably by improving the coagulation and fibrinolysis system and vascular endothelial function of the patients.

Sennoside A(SA),a typical prodrug,exerts its laxative effect only after its transformation into rhei-nanthrone catalyzed by gut microbial hydrolases and reductases.Hydrolases have been identified,but reductases remain unknown.By linking a photoreactive group to the SA scaffold,we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling(ABPP).From lysates of an active strain,Bifidobacterium pseudocatenulatum(B.pseu-docatenulatum),397 proteins were enriched and subsequently identified using mass spectrometry(MS).Among these proteins,chromate reductase/nicotinamide adenine dinucleotide(NADH)phosphate(NADPH)-dependent flavin mononucleotide(FMN)reductase/oxygen-insensitive NADPH nitroreductase(nfrA)was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource(UniProt)database screening.We also determined that recombinant nfrA could reduce SA.Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.

Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in regulating the necroptosis and apoptosis in cerebral ischemia-reperfusion (I/R) injury. However, the regulation of RIPK1 kinase activity after cerebral I/R injury remains largely unknown. In this study, we found the downregulation of protein arginine methyltransferase 1 (PRMT1) was induced by cerebral I/R injury, which negatively correlated with the activation of RIPK1. Mechanistically, we proved that PRMT1 directly interacted with RIPK1 and catalyzed its asymmetric dimethylarginine, which then blocked RIPK1 homodimerization and suppressed its kinase activity. Moreover, pharmacological inhibition or genetic ablation of PRMT1 aggravated I/R injury by promoting RIPK1-mediated necroptosis and apoptosis, while PRMT1 overexpression protected against I/R injury by suppressing RIPK1 activation. Our findings revealed the molecular regulation of RIPK1 activation and demonstrated PRMT1 would be a potential therapeutic target for the treatment of ischemic stroke.

Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling (ABPP). From lysates of an active strain, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 397 proteins were enriched and subsequently identified using mass spectrometry (MS). Among these proteins, chromate reductase/nicotinamide adenine dinucleotide (NADH) phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource (UniProt) database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.