搜索结果：Peptide

Protein and peptide self-assembly is a crucial strategy for bioactive delivery, texture modulation, and food packaging. This review provides a systematic comparative analysis of protein and peptide self-assembly, focusing on intrinsic driving forces, the regulatory effects of external stimuli and coexisting components, the resulting forms of self-assembled products, and the main differences in their applications within food systems. Protein self-assembly is driven by multi-level conformational interactions and synergistic non-covalent forces combined with disulfide bonds, which confers outstanding performance in food texture improvement and preservation. Peptide self-assembly is dominated by amino acid sequences, with sequence-dependent π-π stacking and metal coordination as pivotal tunable driving forces, exhibiting superior advantages in targeted delivery and sensory modulation. Under external regulation, both can form typical assembled structures including nanoparticles, nanofibers, and hydrogels. By harnessing protein and peptide self-assembly, these bottom-up technologies enable food structuring and textural enhancement, opening new avenues for modern food systems.

Peptide-based drug candidates are often susceptible to enzymatic degradation in the gastrointestinal environment and biological matrices, while exhibiting limited intestinal permeability. In developing strategies to overcome these limitations, it is important to quantitatively evaluate the factors contributing to low systemic exposure and to understand the metabolic fate of peptides. This study utilized an integrated analytical approach combining quantitative analysis via liquid chromatography tandem-mass spectrometry (LC-MS/MS) and metabolite profiling via LC-quadrupole time-of-flight MS (LC-QTOF-MS) to characterize the metabolic fate and evaluate the oral dosing feasibility of WKYMVm (Wm), a formyl peptide receptor 2 agonist. A validated LC-MS/MS assay enabled quantification of Wm in mouse plasma with acceptable accuracy (95.2-115.7%) and precision (<8.6%). LC-QTOF-MS analysis identified eight metabolites (M1-M8) in mouse plasma, predominantly formed via sequential N-terminal cleavage with oxidative modifications. Plasma stability data were then simultaneously fitted to a structural parent-metabolite kinetic model, which identified the formation of M4 as the predominant pathway (fraction metabolized (fm)&#x202f;=&#x202f;0.501), followed by M2 (fm&#x202f;=&#x202f;0.262), indicating preferential cleavage at the Lys-Tyr bond. To predict oral dosing feasibility, Caco-2 bi-directional transport data were analyzed using a catenary model, while luminal degradation and hepatic metabolism were estimated using simulated gastric and intestinal fluids and mouse liver S9 fraction. When the experimentally obtained parameters were incorporated into simplified models, the results revealed limited intestinal and hepatic availability under the tested conditions. This integrated analytical and modeling approach identified the metabolic liabilities of Wm, informing the design of Wm analogs to enhance metabolic stability.

Recent experiments have shown that incorporating polyproline segments into arginine (R)-rich cell-penetrating peptides (CPPs) enhances membrane penetration. Here, we employ molecular dynamics (MD) simulations combined with the weighted ensemble approach to investigate how a polyproline segment influences the free-energy barrier for membrane translocation in the designed peptide P9R9. Our results indicate that the extended, conformationally constrained nature of the P9 segment facilitates early membrane engagement and promotes the formation of a hydrated translocation pathway. This behavior is associated with a reduced desolvation penalty during insertion of the arginine-rich (R9) segment. Consistent with this interpretation, the solvent-accessible surface area (SASA) of R9 exhibits a non-monotonic trend, suggesting partial rehydration within the membrane interior. Together, these findings support a sequential translocation mechanism in which P9 interacts with the membrane prior to R9, thereby facilitating subsequent insertion and lowering the free-energy barrier relative to peptides lacking polyproline segments. This work provides a molecular-level perspective on how polyproline segments modulate membrane translocation and offers useful insights for designing more effective CPPs.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes mellitus (T2DM), yet the perioperative safety profile in hand/wrist surgery remains incompletely defined. This study evaluated the association between preoperative GLP-1 RA exposure and postoperative complications and healthcare use following operative fixation of distal radius fractures in adults with T2DM. A retrospective cohort study was performed using the TriNetX Network (2018-2024). Adults with T2DM undergoing open surgical fixation of a distal radius fracture were categorized by active GLP-1 RA use within 180 days preoperatively. Propensity score matching (1:1) balanced demographics, fracture complexity, metabolic factors, diabetes severity, and medication use. Outcomes included 90-day medical complications, 180-day surgical complications, and healthcare use through 180 days. Odds ratios with 95% confidence intervals were estimated by logistic regression. After matching, 1080 patients (540 per cohort) were included. Glucagon-like peptide-1 receptor agonist use was not associated with significant differences in composite 90-day medical complications or composite 180-day surgical complications. Individual adverse events were uncommon and did not differ between groups. Notably, GLP-1 RA use was associated with lower odds of emergency department visit and/or inpatient hospital readmission at 180 days, while use at 30 and 90 days was similar between cohorts. Among adults with T2DM undergoing operative fixation of distal radius fractures, preoperative GLP-1 RA exposure was not associated with increased medical or surgical complications and was associated with reduced 180-day healthcare use. These findings support the perioperative safety of GLP-1 RAs in this setting and warrant prospective validation.

Antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics against multidrug-resistant pathogens, but their application is limited by low yield, structural instability, and potential toxicity. In this study, we designed a hybrid peptide, Aur-Defb3, by fusing a bioinformatically optimized rainbow trout &#x3b2;-defensin-derived sequence with a conserved aurein motif. To improve predicted physicochemical properties, we introduced a Leucine-to-Phenylalanine (L-to-F) substitution into the defensin-derived segment, hypothesizing that the aromatic side chain may contribute to hydrophobic-core stability and membrane interaction. Recombinant Aur-Defb3 was expressed in Komagataella phaffii GS115 and purified by Ni-IDA affinity chromatography. HPLC analysis showed that the major purified peak accounted for 97.08% of the integrated peak area, and the concentration of the purified fraction was estimated by A280 measurement. Antimicrobial assays revealed antibacterial activity against both Gram-positive and Gram-negative bacteria, with MIC values ranging from 31.25 to 250 &#x3bc;g/mL (average 97.7 &#x3bc;g/mL). Hemolysis assays showed low hemolytic activity toward rainbow trout erythrocytes under the tested conditions, with approximately 10% hemolysis observed at 256 &#x3bc;g/mL. Scanning electron microscopy (SEM) showed concentration-dependent morphological damage to bacterial cells, including surface roughening, deformation, and disruption, suggesting that membrane damage may contribute to the antibacterial activity of Aur-Defb3. These results demonstrate the successful expression of Aur-Defb3, supporting its potential for further structural characterization, precise yield quantification, and in vivo mechanistic evaluation.

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing &#x3b2;-cells in the pancreas, leading to absolute insulin deficiency and persistent hyperglycemia. The immune system plays a pivotal role in the development of T1DM, with dendritic cells (DCs) acting as crucial modulators of immune responses. Despite this, the specific role of ADAM19 within the T1DM immune microenvironment remains poorly understood, particularly its expression in DCs and potential effects on pancreatic &#x3b2;-cell function. Further research is needed to explore these aspects in peripheral blood mononuclear cells (PBMCs) and pancreatic tissues. This study aims to investigate the association between ADAM19 expression in DCs and immune features in T1DM. Among the genes consistently upregulated across four independent PBMC transcriptomic datasets and previously implicated in immune regulation, ADAM19 exhibited the most pronounced differential expression in dendritic cell subsets. We therefore focused on ADAM19 to determine whether it influences DC function, thereby disrupting the immune microenvironment and exacerbating pancreatic &#x3b2;-cell damage. Additionally, the study evaluates the potential of ADAM19 as a candidate biomarker for T1DM. This study analyzed public bulk RNA-seq data from peripheral blood mononuclear cells (PBMCs) derived from three datasets (GSE156035, GSE55100, GSE9006), comprising a total of 129 samples (75 T1DM patients and 54 healthy controls). For discovery, an additional in-house PBMC RNA-seq cohort of 20 samples (13 T1DM, 7 controls) was included. Single-cell RNA-seq (scRNA-seq) data were obtained from PBMCs and pancreatic islets, comprising a total of 117 samples (55 from T1DM patients and 62 from healthy controls), with detailed distributions including 46 T1DM and 31 controls from PBMCs, and 9 T1DM and 31 controls from pancreas samples. By integrating transcriptomic and single-cell data, we evaluated the expression patterns of ADAM19 in DCs from T1DM patients. Analytical approaches included partial least squares discriminant analysis (PLS-DA), differential expression analysis (DEG), Gene Set Enrichment Analysis (GSEA), pseudotime trajectory analysis, and cell-cell communication inference to explore the potential involvement of ADAM19 in immune responses. For validation, an independent in-house cohort of PBMC samples (44 samples: 29 T1DM, 15 controls) was examined using RT-qPCR to assess the correlation between ADAM19 expression and C-peptide levels. ADAM19 expression was consistently elevated in PBMCs of T1DM patients across all datasets, with the highest levels observed in DCs in single-cell RNA-seq data. Receiver operating characteristic (ROC) analysis demonstrated AUC values greater than 0.7 in all cohorts, reaching 0.93 in the in-house dataset. Elevated ADAM19 expression in DCs was associated with altered immune cell proportions and reduced fasting C-peptide levels in T1DM patients. This study identifies an association between elevated ADAM19 expression in DCs and T1DM immune features, suggesting potential links to immune dysregulation and &#x3b2;-cell dysfunction. ADAM19 shows promise as a candidate biomarker, warranting further validation for diagnostic and therapeutic applications.

Glucagon-like peptide&#xa0;1 receptor agonists (GLP-1RAs) and dual gastric inhibitory polypeptide (GIP)/GLP-1RAs are used to improve glycaemic control in patients with type&#xa0;2 diabetes mellitus; some of these drugs are also used to help with weight loss. In recent years, safety signals concerning a possible link between GLP-1RA therapies and hair loss have been emerging in the USA. The volume of prescriptions for these drugs in Europe is now increasing, and it can be expected that the number of cases of GLP-1RA-associated hair loss will therefore also increase in Europe over the coming years. In this commentary, we consider the pharmacological context and market expansion for GLP-1RAs, examine the evidence for an association between GLP-1RAs and hair loss, explore potential pathophysiological mechanisms, and propose clinical recommendations. Most evidence suggesting a potential association between GLP-1RAs and hair loss comes from pharmacovigilance database analyses and retrospective cohort studies. No prospective, controlled studies have specifically evaluated this issue. The evidence suggesting an increased risk of hair loss is strongest for semaglutide and tirzepatide. However, although cases of hair loss have been noted across diverse settings and multiple analyses, causality has not been established. One potential underlying mechanism is the rapid weight loss seen with these drugs, which could induce telogen effluvium. Further research is needed to evaluate causality, underlying mechanisms, the role of dosing and route of administration, and patient factors that may increase the risk. Clinicians need to be aware of the possibility of hair loss occurring with GLP-1RAs and patients should be informed about the potential risk and monitored for hair loss.

Many patients with larger bodies present to eating disorder (ED) treatment seeking weight loss. Whether glucose-dependent insulinotropic polypeptide/glucagon-like-peptide receptor agonists (GIP/GLP-1s) are helpful or harmful for such patients remains unknown. This single case experimental design study examined the effects of Tirzepatide (7.5&#xa0;mg/0.05&#xa0;mL), a GIP/GLP-1 following 10-session cognitive-behavioural therapy (CBT-T) in a patient with binge-eating disorder (BED) and obesity. A 37-year-old female presented to an outpatient ED clinic with BED and a body mass index of 68.9&#xa0;kg/m2. We assessed weekly and then monthly ED behaviours and cognitions using the Eating Disorder 15 (ED-15) across two treatment phases: CBT-T (3&#xa0;months) and GIP/GLP-1 administration (9&#xa0;months). As hypothesised, ED cognitions and binge frequency decreased during CBT-T. Also as hypothesised, during GIP/GLP-1 phase, binge frequency remained low and dietary restraint absent. We observed continued reductions in ED cognitions and 39-pound weight loss. GIP/GLP-1 treatment after CBT-T was followed by ED remission and weight loss without serious adverse events. CBT-T skills may mitigate risk of disordered eating during GIP/GLP-1 use. The combination of psychotherapy and GIP/GLP-1s may further reduce binge-eating and lead to weight loss. Research is needed to explore risks and benefits of GIP/GLP-1s for patients&#xa0;with EDs.

In cartilage tissue engineering, successfully mimicking the natural extracellular matrix is essential for promoting hyaline cartilage regeneration. The triple-helix structure of collagen has been identified as a critical element in this process, though preserving this structure while minimizing immunogenicity remains a significant challenge. This study employed high-precision enzymatic digestion technology to specifically remove immunogenic terminal fragments from collagen while preserving its functional triple-helix configuration. The resulting collagen-based hydrogel was engineered with thermosensitive properties, enabling it to adaptively fill irregular cartilage defects and undergo rapid gelation at body temperature. The modified collagen hydrogel demonstrated significantly improved biological safety, with complement activation levels substantially decreasing following removal of terminal peptide segments-confirming the immunogenic role of these regions. Mechanically, the hydrogel successfully replicated the viscoelastic characteristics of natural cartilage, exhibiting matched dynamic mechanical properties capable of cushioning shear-induced damage. Its porous architecture facilitated accelerated nutrient transport while supporting effective cell adhesion and guiding organized proteoglycan deposition with minimal fibrosis. In vivo evaluation revealed a 30.7% higher MOCART score in the experimental group compared to controls, with mechanical properties closely approximating those of healthy native cartilage. Collagen hydrogels that maintain the triple-helix structure represent a highly promising biomaterial platform for cartilage regeneration, combining excellent biocompatibility, functional mechanical properties, and significant tissue repair capability while effectively addressing the critical challenge of immunogenicity through targeted terminal peptide removal.

Trichinella spiralis is a zoonotic nematode responsible for trichinellosis, a disease with significant public health and economic implications. The current treatment of trichinellosis has limited efficacy, so the development of novel therapeutic agents is essential for effective parasite control. Scorpion venoms contain active compounds, including antimicrobial peptides (AMPs), which have efficacy against a variety of microbes principally through membrane destruction. In this study, the in vitro anti-parasitic effects of Smp24 and Smp43, scorpion venom-derived AMPs, were evaluated against T. spiralis through toxicity assays, ultrastructural analysis, molecular docking, and gene expression profiling. In vitro toxicity assays demonstrated significant inhibitory effects of Smp24 and Smp43 (0-100&#x3bc;g/mL) against adult worms and muscle larvae in a dose- dose-time dependent manner. Ultrastructural SEM analysis after treatment of either Smp24 or Smp43 at LC50 concentrations for 48 hours revealed extensive morphological and structural damage in treated parasites, including disruption of the cuticle, indicating a direct cytotoxic effect. Molecular docking studies predicted strong binding interactions between Smp24, Smp43, and T. spiralis thymidylate synthase, suggesting inhibition of DNA synthesis as a potential mechanism of action. Moreover, gene expression revealed significant upregulation in apoptosis-related genes (Casp3, Casp9, P53) and downregulation of oncogene marker (Ras) in both T. spiralis adult worms and muscle larvae after treatment with the LC50 of Smps peptides, indicating the induction of apoptosis. These findings highlight the potent antiparasitic activity of Smp24 and Smp43 through multiple mechanisms, including direct toxicity, thymidylate synthase inhibition, and apoptotic cell death, suggesting they are promising candidates for controlling T. spiralis infections.

Scallop aquaculture is increasingly threatened by larval mortality caused by Vibrio bacteria, highlighting the need for sustainable pathogen control strategies. In a previous study, we designed and synthesized two novel cationic antimicrobial peptides (AMPs) derived from Argopecten purpuratus, a key scallop species in Chilean and Peruvian aquaculture, namely Helixidin and N-ter ApBD Q13R. These AMPs exhibited strong antibacterial activity and distinct mechanisms of action against host-associated vibrio strains while being innocuous to scallop larvae. In the present study, we evaluated the therapeutic potential of these synthetic AMPs, administered individually and in combination, in A. purpuratus veliger and pediveliger larvae experimentally infected with the pathogenic strain Vibrio bivalvicida VPAP30, and explored the potential mechanisms underlying their protective effects. Our results demonstrated that (i) Helixidin and N-ter ApBD Q13R significantly increased larval survival following VPAP30 infection; (ii) this protective effect is partly explained by their direct inhibition of VPAP30 growth; (iii) the combination of both AMPs upregulates immune-related genes associated with the TLR-I&#x3ba;B-BD pathway in uninfected pediveliger larvae, suggesting a potential immune-priming effect; and (iv) in silico analyses revealed potential molecular interactions between the AMPs and Gram-negative bacterial membranes, as well as with the pattern recognition receptor ApTLR. These findings suggest that Helixidin and N-ter ApBD Q13R represent a promising and sustainable strategy for managing Vibrio infections in scallop aquaculture, aligning with broader goals of maintaining healthy marine ecosystems and supporting industry sustainability.

Calcitonin gene-related peptide (CGRP) monoclonal antibodies have transformed migraine prevention, but their efficacy in cluster headache remains uncertain. We searched PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov through February 28, 2026, for trials of CGRP monoclonal antibodies in cluster headache. The primary outcome was weekly cluster headache attack frequency, quantified as mean difference (MD) with 95% confidence intervals. Bayesian meta-analysis with five prior specifications and trial sequential analysis were conducted as prespecified sensitivity analyses. Four trials (655 participants) were included. The pooled MD was -&#xa0;0.81 attacks per week (95%CI -&#xa0;2.24 to 0.62; P&#x2009;=&#x2009;0.265; I2&#x2009;=&#x2009;8%). Neither episodic (MD -&#xa0;1.21; 95%CI -&#xa0;5.20 to 2.78) nor chronic (MD -&#xa0;0.93; 95%CI -&#xa0;2.89 to 1.03) subgroups reached significance (P&#x2009;=&#x2009;0.90). The odds ratio for 50% or greater responder rate was 1.39 (95%CI 0.88-2.19; P&#x2009;=&#x2009;0.159); risk ratios reached significance (1.25; 95%CI 1.04-1.49; P&#x2009;=&#x2009;0.017), a discrepancy driven by high placebo rates (27-53%). Bayesian analysis showed an 81.1% posterior probability of any benefit, but only 17.9% probability that the true reduction reached 2 or more attacks per week. Trial sequential analysis indicated that for an assumed effect of 2.5 attacks per week, accrued information exceeded the required information size (135.6%) without the cumulative Z-statistic crossing the efficacy boundary; for an assumed effect of 2.0, evidence remained inconclusive. Current evidence is insufficient to determine significant benefit of CGRP monoclonal antibodies in cluster headache. Modest benefit cannot be excluded, but clinically meaningful efficacy remains uncertain.

Immediate bleeding after endoscopic sphincterotomy (EST) is a common adverse event during ERCP. However, the optimal first-line hemostatic strategy remains undefined because comparative randomized trials are lacking. We aimed to evaluate the non-inferiority of a self-assembling peptide (SAP)-first strategy compared with conventional balloon tamponade for oozing-type immediate post-EST bleeding, with superiority testing performed as a pre-specified exploratory analysis. PROTECT-EST was a multicenter, investigator-initiated, parallel-group randomized controlled trial conducted at tertiary referral centers in Japan. Adults with oozing-type bleeding persisting for &#x2265;180 seconds after EST without spontaneous hemostasis were randomly assigned (1:1) to SAP application or balloon tamponade as the initial hemostatic strategy. The primary endpoint was successful initial hemostasis, defined as the absence of active oozing for &#x2265;3 minutes after the assigned intervention. Noninferiority was tested first, and superiority was assessed as a prespecified exploratory analysis. A total of 130 patients were randomized (SAP group, n=65; balloon group, n=65). SAP met the prespecified noninferiority criterion. In the prespecified exploratory superiority analysis, successful initial hemostasis occurred in 60 of 65 patients (92.3%) in the SAP group and 50 of 65 patients (76.9%) in the balloon group (risk difference, 15.4 percentage points; 95% confidence interval, 3.1-27.7; P=0.027). The mean time to completion of the initial hemostatic intervention was shorter in the SAP group, and rescue hemostatic devices were required less frequently (7.7% vs 23.1%; P=0.033). Adverse events and delayed hemorrhage were similar between groups. In supportive bootstrap-based economic analyses, the SAP-first strategy was generally more effective and not more costly. In this noninferiority trial, a SAP-first strategy was noninferior to balloon tamponade for oozing-type immediate post-EST bleeding and, in exploratory analyses, was associated with higher initial hemostasis, shorter procedure time, and less rescue device use. SAP may represent a practical first-line option, although external validation is warranted.

Targeting the transferrin receptor (TfR) holds promise for drug delivery across the blood-brain barrier (BBB), but conventional strategies suffer from competition with endogenous ligands and suboptimal trafficking. To overcome these limitations, we engineered a library of T7 peptide-functionalised pH-responsive polymersomes with precise control over ligand density and ligand insertion depth (&#x3b4;) within a poly(ethylene glycol) (PEG) corona. We generated nanoparticles with &#x3b4; values ranging from 0.3 (deeply inserted ligands) to 1.0 (fully exposed ligands), enabling systematic evaluation of how spatial ligand presentation influences BBB interactions. In vitro studies revealed that &#x3b4;&#x2009;=&#x2009;1.0 polymersomes exhibited efficient transcytosis, whereas &#x3b4;&#x2009;=&#x2009;0.6 polymersomes promoted endothelial retention, a divergence likely linked to differential receptor clustering and trafficking kinetics. Notably, TfR-mediated transport occurred independently of PACSIN2, distinguishing it from tubular transcytosis pathways observed with LRP1-targeted systems. These findings establish avidity-by-design as a strategy to tailor nanocarriers for either BBB penetration or vascular targeting, offering a modular platform for neurological therapeutics.

Endometriosis progression is driven by oxidative stress and excessive angiogenesis within an inflammatory microenvironment. To overcome these challenges, we designed ROS/pH dual-responsive Alpelisib-loaded nanoparticles (Alp@TAT-AT7-NPs) functionalized with an anti-NRP1 peptide for targeted therapy. The nanoparticles exhibited superior stability, responsive drug release, and selective internalization by NRP1-overexpressing endothelial cells. In vitro results showed efficient inhibition of NRP1 and downstream PI3K/AKT signaling, along with decreased reactive oxygen species (ROS) and enhanced antioxidant enzyme activities. In an endometriosis rat model, treatment with Alp@TAT-AT7-NPs significantly reduced ectopic lesion burden and angiogenic markers (VEGF, CD34), while suppressing systemic inflammation and oxidative injury indicators such as IL-6, TNF-&#x3b1;, and MDA. Fluorescence imaging confirmed preferential accumulation of nanoparticles in CD31&#x207a; vascular regions. Mechanistic studies demonstrated that modulation of the Sema3A-NRP1-PI3K/AKT signaling axis restored redox homeostasis and inhibited pathological angiogenesis. These findings identify Alp@TAT-AT7-NPs as a synergistic nanoplatform that integrates microenvironment responsiveness with NRP1-targeted intervention, providing a promising therapeutic strategy for endometriosis.

Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy is commonly used for esophageal squamous cell carcinoma in Japan, but it often causes chemotherapy-induced diarrhea (CID), thus impairing the quality of life. We investigated the association between a trace element-enriched collagen peptide beverage (CP10) and CID during DCF therapy. This retrospective study included 94 patients who underwent radical esophagectomy following DCF therapy (January 2023-December 2025). During the first DCF cycle, 26 patients consumed CP10 daily (CP+ group), whereas 68 did not (CP- group). The primary endpoint was CID incidence during the first DCF cycle, assessed using the Common Terminology Criteria for Adverse Events. A multivariable logistic regression analysis was performed to adjust for any potential confounders. Grade&#x2009;&#x2265;&#x2009;1, &#x2265;2, and &#x2265;&#x2009;3 CID occurred in 15%, 15%, and 12% of the CP+ group versus 46%, 38%, and 32% of the CP- group, respectively. CP10 use was associated with a lower incidence of CID across all severity grades. In the multivariable analysis, this association remained statistically significant for grade&#x2009;&#x2265;&#x2009;1 CID (adjusted OR 0.22, 95% CI 0.05-0.74; P&#x2009;=&#x2009;0.013). Sensitivity analyses yielded consistent estimates (adjusted OR 0.15-0.28). CP10 use was associated with a lower incidence of CID during DCF therapy.

The Shono oxidation stands as a premier electrochemical method for the &#x3b1;-C-H functionalization of amines. While glycine esters serve as ideal substrates with immense synthetic potential, their electrochemical derivatization has historically been restricted primarily to C-C and C-P bond formation. Herein, we report the first electrochemical strategy for the direct N-heteroarylation of &#x3b1;-C-H bonds in Gly-containing natural products, drug molecules, and peptides via a controllable anodic oxidation pathway under transition-metal-free conditions. At the same time, modified target product 3x exhibited good inhibitory activities toward the SKOV3 and MDA-MB-231 cell lines, with IC50 values of 9.94 &#xb1; 1.46 and 17.11 &#xb1; 3.67, respectively, far superior to the antitumor activities of unmodified substrate 1a (IC50 > 50). Therefore, besides synthetic applications, this method also provides new possibilities for discovering potentially bioactive molecules.

Obesity and autoimmune diseases (AIDs) are each associated with elevated risk of cardiovascular and thromboembolic events. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiovascular and metabolic benefits in patients with type 2 diabetes and obesity, but their effects in patients with obesity and comorbid AID remain uncertain. This study evaluated the association between GLP-1RA use and major adverse cardiovascular and thromboembolic event risk among adults with obesity and AID. This retrospective cohort study emulated a target trial using 2014 to 2024 electronic health record data from the OneFlorida+ network. Adults (aged &#x2265;18&#x2009;years) with AID and obesity eligible for antiobesity medication therapy were included. Exposure was defined as GLP-1RA use versus nonuse. Participants were matched using 1:1 time-dependent propensity scores. The primary outcomes were myocardial infarction, stroke or transient ischemic attack, pulmonary embolism, venous thromboembolism, and coronary revascularization. Secondary outcomes included hospitalization, emergency department visits, and all-cause mortality. We matched 13&#x2009;204 GLP-1RA users and 13&#x2009;204 nonusers (mean &#xb1; SD age, 54.7&#x2009;&#xb1;&#x2009;14.5&#x2009;years; 73.4% women; mean body mass index, 37&#x2009;kg/m2). GLP-1RA use was associated with lower hazard of stroke/transient ischemic attack (hazard ratio [HR], 0.87 [95% CI, 0.76-0.99]; P=0.039), pulmonary embolism (HR, 0.69 [95% CI, 0.56-0.86]; P=0.001), venous thromboembolism (HR, 0.83 [95% CI, 0.72-0.95]; P=0.007), emergency department visits (HR, 0.79 [95% CI, 0.75-0.83]; P<0.001), and mortality (HR, 0.56 [95% CI, 0.47-0.66]; P<0.001). Among adults with obesity and AID, GLP-1RA use was associated with reduced thromboembolic events, lower emergency department use, and decreased mortality, suggesting potential cardiovascular and survival benefits in this high-risk population.