Peptide-drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug-target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (>10¹³ variants). This approach, using site-specific incorporation of N-chloroacetyl-d-phenylalanine and fluorosulfate-l-tyrosine, accelerated the discovery of irreversibly binding (K _i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ via proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.

This study aimed to investigate whether β-elemene could improve the dysfunction of vascular endothelial cells induced by low shear force (LSS), and the proliferation and migration of vascular smooth muscle cells induced by oxidized low-density lipoprotein (ox-LDL). Parallel plate flow chambers and ox-LDL were used to establish vascular endothelial cells (ECs) dysfunction model and vascular smooth muscle cell (VSMCs) proliferation and migration model, respectively, and the effects of β-elemene on ECs dysfunction and VSMCs proliferation and migration were examined. The activity of ROS in ECs was measured by DHE and the activity of NO in ECs was tested by DAF-FM DA. The protein phosphorylation of Akt and ERK in ECs were detected by Western blot. The proliferation of VSMCs was measured by MTT. The migration of VSMCs was examined by cell scratch test and Transwell assay. The gene expression of MMP-2 and MMP-9 in VSMCs was measured by RT-qPCR. In ECs, β-elemene could significantly reduce the LSS-induced increase in ROS, significantly increase the LSS-induced decrease in NO, decrease the phosphorylation of ERK, and increase the phosphorylation of Akt. In VSMCs, β-elemene could significantly reduce the proliferation and migration of VSMCs induced by ox-LDL, and reduce the gene expression of MMP-2 and MMP-9. To conclude, β-elemene can improve the LSS-induced ECs dysfunction and ox-LDL-induced VSMCs proliferation and migration.

To explore the relationship between plasma amyloid?β (Aβ) and cognitive decline during 2 year follow?up in a population?based cohort in Xi′an rural areas. Methods The study was conducted in Qubao village in Xi′an suburbs cognitively normal residents over 40 years old were recruited from October 2014 to March 2015 and given a face?to?face standardized interview. Mini?mental state examination (MMSE) was employed to evaluate the global cognitive function, and quantification of plasma Aβ was measured by sandwich enzyme?linked immunosorbent assay (ELISA) at baseline. Two years later, MMSE was tested at the end of study. Then logistic regression was performed to analyze the relationship between baseline Aβ and cognitive change during 2 year follow?up. Results A total of 1 020 participants completed the study, among whom 223 subjects (21.9%) presented MMSE scores decline (defined as MMSE scores decreased≥2 points). Compared with those without decline, participants in the MMSE decline group were older (P<0.001) and had lower education level (P<0.001), while gender, hypertension, hyperlipemia, diabetes mellitus and APOE genotype were not significantly different between two groups. One?way analysis of variance (ANOVA) showed that the MMSE score decline was slighter in the lower tertile of baseline Aβ1?40 compared with middle tertile (P=0.012), while MMSE decline were similar between different A β 1?42 level groups and A β 1?42/A β 1?40 ratio groups (P=0.758, P=0.671, respectively). Multivariable logistic regression analysis showed that MMSE scores in the lower baseline plasma A β 1?40 level declined more slowly (OR=0.565, 95%CI 0.379-0.845, P=0.005). However, the MMSE decline were also similar among different baseline plasma Aβ1?42 levels groups and Aβ1?42/Aβ1?40 ratio groups. Conclusion Population with lower level of baseline plasma Aβ1?40 manifests lower cognitive decline during 2 years, however further investigation on dynamics of plasma Aβ and long term follow up are needed.

Objective: To explore the relationship between plasma amyloid-β (Aβ) and cognitive decline during 2 year follow-up in a population-based cohort in Xi′an rural areas. Methods: The study was conducted in Qubao village in Xi′an suburbs cognitively normal residents over 40 years old were recruited from October 2014 to March 2015 and given a face-to-face standardized interview. Mini-mental state examination (MMSE) was employed to evaluate the global cognitive function, and quantification of plasma Aβ was measured by sandwich enzyme-linked immunosorbent assay (ELISA) at baseline. Two years later, MMSE was tested at the end of study. Then logistic regression was performed to analyze the relationship between baseline Aβ and cognitive change during 2 year follow-up. Results: A total of 1 020 participants completed the study, among whom 223 subjects (21.9%) presented MMSE scores decline (defined as MMSE scores decreased ≥2 points). Compared with those without decline, participants in the MMSE decline group were older (P<0.001) and had lower education level (P<0.001), while gender, hypertension, hyperlipemia, diabetes mellitus and APOE genotype were not significantly different between two groups. One-way analysis of variance (ANOVA) showed that the MMSE score decline was slighter in the lower tertile of baseline Aβ₁-40 compared with middle tertile (P=0.012), while MMSE decline were similar between different Aβ₁-42 level groups and Aβ_1-42/Aβ_1-40 ratio groups (P=0.758, P=0.671, respectively). Multivariable logistic regression analysis showed that MMSE scores in the lower baseline plasma Aβ_1-40 level declined more slowly (OR=0.565, 95%CI 0.379-0.845, P=0.005). However, the MMSE decline were also similar among different baseline plasma Aβ_1-42 levels groups and Aβ_1-42/Aβ_1-40 ratio groups. Conclusion Population with lower level of baseline plasma Aβ_1-40 manifests lower cognitive decline during 2 years, however further investigation on dynamics of plasma Aβ and long term follow up are needed.

Objective To evaluate the relationship between endothelin-1 (ET-1) and p38 mitogenactivated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathways during mechanical stretch-induced enhancement of adhesion of rat pulmonary microvascular endothelial cells (PMVECs).Methods Rat PMVECs were seeded in the culture plate at a density of 0.5×105 cells/ml (2 ml/well) and divided into 5 groups (n=24 each) using a random number table:control group (group C),mechanical stretch group (group MS),mechanical stretch plus specific PI3K inhibitor LY294002 group (LY group),mechanical stretch plus specific p38 MAPK inhibitor SB203580 group (SB group),and mechanical stretch plus selective ETA receptor blocker BQ123 group (BQ group).Cells were exposed to 20％ cyclic stretch at 0.3 Hz for 4 h using a sine wave.In LY,SB and BQ groups,LY294002,SB203580 and BQ123 at the final concentration of 10 μmol/L were added,respectively,after mechanical stretch,cells were incubated for 10 min,and then extracted and purified rat polymorphonuclear neutrophil leukocytes (PMNs,5× 105 cells/well) were added and co-incubated with PMVECs for 30 min and then washed out.The concentrations of ET-1 and interleukin-6 (IL-6) in the culture medium were determined using enzyme-linked immunosorbent assay.The expression of phosphorylated p38 MAPK (p-p38 MAPK) and phosphorylated Akt (p-Akt) was detected by Western blot.Adhesion of PMNs was measured by immuno-histochemistry,and the adhesion rate was calculated.The expression of P-selectin mRNA was detected using real-time polymerase chain reaction.Results Compared with group C,the concentrations of IL-6 and ET-1 in the culture medium were significantly increased,the expression of p-p38 MAPK,p-Akt and P-selectin mRNA was up-regulated,and the adhesion rate of PMNs was increased in the other four groups (P＜0.05).Compared with group MS,the concentration of IL-6 in the culture medium was significantly decreased,the expression of p-Akt and P-selectin mRNA was down-regulated,and the adhesion rate of PMNs was decreased in LY,SB and BQ groups,the concentration of ET-1 in the culture medium was significantly decreased in group BQ,and the expression of p-p38 MAPK was significantly down-regulated in SB and BQ groups (P＜0.05).Conclusion The signaling mechanism underlying ET-1-mediated enhancement of rat PMVEC adhesion may be related to activating p38 MAPK and PI3K/Akt signaling pathways.