摘要：
Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented. This work introduces the role of peptides in immune regulation of innate and adaptive immune cells, as well as immune checkpoints. Then this work introduces two strategies for delivering polypeptides: peptide self-assemblies, and peptide-functionalized nanocarriers. Finally, the challenges and prospects of peptides in tumor immunotherapy are summarized. image
期刊：
JOURNAL OF ORGANIC CHEMISTRY,2025年90(4):1656-1662 ISSN：0022-3263
通讯作者：
Lei, Zhengwen;Wang, Zhen;Zeng, YF;Wang, Z
作者机构：
[Shen, Lixian] Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Pharm,Hunan Prov Key Lab Basic & Clin Pharmac, Hengyang 421001, Hunan, Peoples R China.;[Shen, Lixian; Liu, Jie; Wang, Zhen; Peng, Xue; Lei, Zhengwen; Zeng, Yao-Fu; Lei, ZW] Univ South China, Affiliated Hosp 1, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Wang, Zhen] Univ South China, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.;[Wang, Zhen] Chinese Acad Sci, Northwest Inst Plateau Biol, Qinghai Prov Key Lab Tibetan Med Res, Xining 810008, Qinghai, Peoples R China.
通讯机构：
[Wang, Z; Zeng, YF ; Wang, Z ; Lei, ZW] U;Univ South China, Affiliated Hosp 1, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.;Chinese Acad Sci, Northwest Inst Plateau Biol, Qinghai Prov Key Lab Tibetan Med Res, Xining 810008, Qinghai, Peoples R China.
摘要：
We report a photoredox-catalyzed three-component sulfonaminoalkynylation of alkenes with N -aminopyridine salts and potassium alkynyltrifluoroborate salts. This aminoalkylation reaction underwent a radial/polar crossover mechanism, which was distinguished from the previous reports. A variety of β-alkynylated sulfonamides were obtained in moderate to excellent yields. The versatility of this method was further evidenced by its successful application in modifying biological molecules in advanced stages of development.
We report a photoredox-catalyzed three-component sulfonaminoalkynylation of alkenes with N -aminopyridine salts and potassium alkynyltrifluoroborate salts. This aminoalkylation reaction underwent a radial/polar crossover mechanism, which was distinguished from the previous reports. A variety of β-alkynylated sulfonamides were obtained in moderate to excellent yields. The versatility of this method was further evidenced by its successful application in modifying biological molecules in advanced stages of development.
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摘要：
The monocyte adhesion to vascular endothelial cells constitutes a key step in atherosclerosis pathogenesis. We previously found that ROS-autophagy pathway participated in the monocyte-endothelial cell adhesion induced by angiotensin domain type 1 receptor-associated proteins (APJ) and its endogenous ligand apelin-13. In this study, we investigated what specific type of autophagy apelin-13 regulated in this process. By conducting full-scale transcriptomic analysis in apelin-13-treated human umbilical vein endothelial cells (HUVECs), we found that the transcription levels of ER-phagy receptor protein SEC62 were significantly elevated. Importantly, SEC62 was also upregulated in human atherosclerotic lesions. Thus, we investigated the effects of SEC62-dependent ER-phagy on apelin-13-induced monocyte-endothelial cell adhesion and atherosclerosis pathogenesis. We demonstrated that Apelin-13 (0.001-1 μM) dose-dependently upregulated SEC62 expression thereby inducing ER-phagy in HUVECs. This effect was reversed by autophagy inhibitor 3MA (10 mM) and endoplasmic reticulum stress inhibitor salubrinal (10 μM). The siRNA-Sec62, 3MA (10 mM), and salubrinal (10 μM) all inhibited apelin-13-induced monocyte-endothelial cells adhesion, whereas vascular endothelial cells specific SEC62 deletion alleviated atherosclerotic plaques area, intercellular adhesion molecules expression and lesional macrophages in apelin-13-treated APOE(-/-) mice with high-fat and high-cholesterol diet. Moreover, we demonstrated that ubiquitin-like modification of ALDH1L1 was involved in SEC62-dependent ER-phagy in apelin-13-treated HUVECs: apelin-13 upregulated small ubiquitin-like protein UBL4A, which mediated the ubiquitination-like modification of ALDH1L1 at 812-lysine site. This, in turn, promoted insertion of ALDH1L1 into ER membrane and led to SEC62-dependent ER-phagy. We showed that siRNA-UBL4A, siRNA-ALDH1L1, siRNA-ASNA1, and the mutant of 812 lysine site of ALDH1L1 all decreased apelin-13-induced monocyte-endothelial cell adhesion. We conclude that apelin-13 induces SEC62-dependent ER-phagy to promote monocyte-endothelial cell adhesion and atherosclerosis. This study reveals new mechanisms underlying atherosclerosis and identifies a potential therapeutic target.
摘要：
Microcystin-LR (MC-LR) is a toxin that causes hepatic steatosis. Our previous study found that exposure to 60 μg/L MC-LR for 9 months resulted in liver lipid accumulation, but the underlying mechanisms remain elusive. Herein, for the first time, fatty acid-targeted metabolome and RNA-seq were combined to probe the effect and mechanism of chronic (12-month) MC-LR treatment on mice lipid metabolism at environmental-related levels (1, 60, and 120 μg/L). It was found that MC-LR dose-dependently raised serum and liver lipid levels. The total cholesterol (TC) levels in the liver were significantly increased following treatment with 1 μg/L MC-LR (equivalent to 0.004 μ/L in human). Treatment with 60 and 120 μg/L MC-LR significantly elevated TC and triglyceride (TG) levels in both serum and liver. Serum fatty acid-targeted metabolome analysis demonstrated that exposure to 1, 60, and 120 μg/L MC-LR caused significant alterations in the fatty acid profile. Chronic 1, 60, and 120 μg/L MC-LR treatment significantly increased serum polyunsaturated fatty acids (PUFAs), including conjugated linoleic acid and eicosapentaenoic acid, which positively correlated with serum or liver TG levels. Chronic exposure to 120 μg/L MC-LR led to a significant decrease in the accumulation of saturated fatty acids, including citramalic acid, pentadecanoic acid, and docosanoic acid, which were negatively correlated with serum or liver lipid levels. These findings suggested that 1 μg/L MC-LR exposure caused mild lipid metabolism disruption, while 60 and 120 μg/L MC-LR treatment resulted in pronounced hepatic steatosis in mice. Transcriptome analysis revealed that chronic environmental MC-LR treatment regulated the expression of genes involved in the phosphatidylinositol 3-kinase (PI3K) complex and fatty acid metabolism. Western blotting and RT-qPCR confirmed that chronic environmental MC-LR exposure activated the PI3K/AKT/mTOR signaling pathway, the downstream of fads3 gene that participates in fatty acid desaturation was upregulated, fatty acid degradation-related genes, including acsl1, acsl4, and ehhadh were inhibited, and lipid transport-related genes, including slc27a4 and apol7a, were promoted. Thus, chronic environmental MC-LR exposure boosts hepatic steatosis. Our work indicated that the limit concentration of 1 μg/L MC-LR in human drinking water for safety needs to be discussed. The study provides the first evidence of the fatty acid profile and gene changes and gains new insights into the mechanisms of chronic environmental MC-LR treatment-induced hepatic steatosis.
作者机构：
[Liu, Ying; Deng, Min; Zhai, Zibo; He, Longwei; Wang, Peipei; Li, Songjiao; Cheng, Dan; He, LW] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Dept Pharm & Pharmacol, Hengyang 421002, Peoples R China.;[Cheng, Dan] Univ South China, Affiliated Nanhua Hosp, Clin Res Inst, Hengyang Med Sch,Dept Gastroenterol, Hengyang 421002, Peoples R China.;[He, LW; He, Longwei] Henan Normal Univ, Sch Chem & Chem Engn, Xinxiang 453007, Peoples R China.
通讯机构：
[He, LW ] H;[Li, SJ ; He, LW] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Dept Pharm & Pharmacol, Hengyang 421002, Peoples R China.;Henan Normal Univ, Sch Chem & Chem Engn, Xinxiang 453007, Peoples R China.
摘要：
Revealing changes in the tumor microenvironment is crucial for understanding cancer and developing sensitive methods for precise cancer imaging and diagnosis. Intracellular hydrogen peroxide (H(2)O(2)) and microenvironmental factors (e.g., viscosity and polarity) are closely linked to various physiological and pathological processes, making them potential biomarkers for cancer. However, a triple-response theranostic probe for precise tumor imaging and therapy has not yet been achieved due to the lack of effective tools. Herein, we present a mitochondria-targeting near-infrared (NIR) fluorescent probe, VPH-5DF, capable of simultaneously monitoring H(2)O(2), viscosity, and polarity through dual NIR channels. The probe specifically detects H(2)O(2) via NIR emission (λ(em) = 650 nm) and shows high sensitivity to microenvironmental viscosity/polarity in the deep NIR channel (λ(em) ≈ 750 nm). Furthermore, the probe not only monitors mitochondrial polarity, viscosity, and fluctuations in endogenous/exogenous H(2)O(2) levels but also distinguishes cancer cells from normal cells through multiple parameters. Additionally, VPH-5DF can be employed to monitor alterations in H(2)O(2) levels, as well as changes in viscosity and polarity, during drug-induced pyroptosis in living cells. After treatment with VPH-5DF, chemotherapy-induced oxidative damage to the mitochondria in tumor cells activated the pyroptosis pathway, leading to a robust antitumor response, as evidenced in xenograft tumor models. Thus, this triple-response theranostic prodrug offers a new platform for precise in vivo cancer diagnosis and anticancer chemotherapy.
作者机构：
[Wang, Jikai; Zeng, Pengfei; He, Suisui; Xiao, Xilin] Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China;[Xie, Haitao] Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China;Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha, 410006, China;[Yu, Cuiyun] Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China<&wdkj&>Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha, 410006, China
通讯机构：
[Jikai Wang] H;Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
摘要：
Aptamers have recently become novel probes for biosensors because of their good biocompatibility, strong specificity, and high sensitivity. Biosensors based on peptides or nucleic acid aptamers are used in implantable and wearable devices owing to their ease of synthesis and economic efficiency. Simultaneously, amphoteric ionic peptides are being explored as antifouling layers for biosensors resistant to interference from extraneous proteins in serum. Thus, this paper reviews recently developed aptamer-based biosensors and introduces peptide- and nucleic acid-based biosensors, while focusing on the three primary classes of biosensors: electrochemical sensors, fluorescent or colorimetric biosensors, and electroluminescent sensors. Furthermore, we summarize their general construction strategies, describe specific electrochemical sensors that use peptides as an antipollution layer, and elucidate their advantages.
摘要：
There is relatively little research on cyclic amphiphilic block polymers, having both hydrophilic and hydrophobic segments placed in the ring and thus resulting in a higher degree of topological restriction, as drug vehicles. Cyclic amphiphilic binary block polymer is synthesized by the click coupling reaction of bimolecular homodifunctional precursors. The results indicate that cyclization between linear polymer precursors is successful if the trace linear by-products generated are ignored, which also suggests that the small molecule bifunctional terminating agent applied in traditional bimolecular homodifunctional ring-closure process can be extended to large molecule. Moreover, the study on the self-assembly behavior of polymers shows that, compared with linear counterparts, the stability and drug loading capacity of micelles based on the resultant cyclic polymer are not significantly improved due to the influence of topological structure and linear impurities. Nevertheless, drug loaded micelles formed by the obtained cyclic polymers still exhibit superior cellular uptake ability. It can be seen that topological effects do play an irreplaceable role in the application performance of polymers. Therefore, the construction and synthesis of cyclic and its derivative polymers with moderate topological confinement and high purity may be a key direction for future exploration of polymer drug delivery carriers.
摘要：
Therapeutic challenges of chronic pulmonary infections caused by multidrug-resistant Pseudomonas aeruginosa (MDR P. aeruginosa ) biofilms due to significantly enhanced antibiotic resistance. This resistance is driven by reduced outer membrane permeability, biofilm barriers, and excessive secretion of virulence factors. Thickened mucus in the airways exacerbates the problem by impeding antibiotic penetration, providing a breeding ground for biofilms, consequently aggravating infection. Moreover, biofilms recruit numerous immune cells, resulting in chronic inflammation and lung tissue damage. In turn, damaged airway further facilitates bacterial colonization and elevated mucus production. To thoroughly disintegrate the stubborn triad of “thickened mucus & dense biofilm & excessive inflammation” and address drug resistance, tailored multilayer nanoparticles (NPVC/PBIP NPs) were developed. NPVC/PBIP NPs were engineered through self-assembly of vanillin-chitosan amphiphilic polymer loading polymyxin B-linoleic acid ion pairs in. Then polyaspartic acid and N -acetylcysteine-ε-poly- l -lysine were coated by layer-by-layer on the surface of vanillin-chitosan NPs via electrostatic interactions. As expected, the NAC units on NPVC/PBIP NPs effectively thinned human clinical sputum and porcine sputum, resulting in rapid sputum penetration followed by biofilm permeation. NPVC/PBIP NPs achieved over 99 % eradication of mature biofilms in vitro . Furthermore, they effectively inhibited virulence factors production and bacteria re-adhesion (biofilm reformation) while exhibiting superior anti-inflammatory and antioxidant activities. In a chronic pulmonary infection model, NPVC/PBIP NPs remarkably thinned airway mucus, reduced bacterial burden by 99.7 %, alleviated inflammatory cell infiltration, and minimized lung tissue damage. In summary, the NPVC/PBIP NPs represent a novel and promising strategy to manage MDR P. aeruginosa biofilms associated infections by disintegrating the stubborn triad of “thickened mucus & dense biofilm & excessive inflammation”.
Therapeutic challenges of chronic pulmonary infections caused by multidrug-resistant Pseudomonas aeruginosa (MDR P. aeruginosa ) biofilms due to significantly enhanced antibiotic resistance. This resistance is driven by reduced outer membrane permeability, biofilm barriers, and excessive secretion of virulence factors. Thickened mucus in the airways exacerbates the problem by impeding antibiotic penetration, providing a breeding ground for biofilms, consequently aggravating infection. Moreover, biofilms recruit numerous immune cells, resulting in chronic inflammation and lung tissue damage. In turn, damaged airway further facilitates bacterial colonization and elevated mucus production. To thoroughly disintegrate the stubborn triad of “thickened mucus & dense biofilm & excessive inflammation” and address drug resistance, tailored multilayer nanoparticles (NPVC/PBIP NPs) were developed. NPVC/PBIP NPs were engineered through self-assembly of vanillin-chitosan amphiphilic polymer loading polymyxin B-linoleic acid ion pairs in. Then polyaspartic acid and N -acetylcysteine-ε-poly- l -lysine were coated by layer-by-layer on the surface of vanillin-chitosan NPs via electrostatic interactions. As expected, the NAC units on NPVC/PBIP NPs effectively thinned human clinical sputum and porcine sputum, resulting in rapid sputum penetration followed by biofilm permeation. NPVC/PBIP NPs achieved over 99 % eradication of mature biofilms in vitro . Furthermore, they effectively inhibited virulence factors production and bacteria re-adhesion (biofilm reformation) while exhibiting superior anti-inflammatory and antioxidant activities. In a chronic pulmonary infection model, NPVC/PBIP NPs remarkably thinned airway mucus, reduced bacterial burden by 99.7 %, alleviated inflammatory cell infiltration, and minimized lung tissue damage. In summary, the NPVC/PBIP NPs represent a novel and promising strategy to manage MDR P. aeruginosa biofilms associated infections by disintegrating the stubborn triad of “thickened mucus & dense biofilm & excessive inflammation”.
摘要：
PURPOSE: Immune checkpoint inhibitors (ICIs) have significantly changed cancer therapy, improving patient survival rates and clinical outcomes. Nevertheless, the use of PD-1/PD-L1 inhibitors can result in immune-related adverse events (irAEs). This study aims to investigate the prevalence and associated risk factors of irAEs in a real-world setting, as well as to assess their effects on optimal therapeutic outcomes. METHODS: A retrospective analysis involved 2523 patients with cancer who received inpatient PD-1/PD-L1 inhibitors treatment between January 2018 and December 2022. We documented patients' demographic and clinical characteristics, PD-1 or PD-L1 inhibitors, treatment modalities, incidences, timing, and severity of irAEs, and efficacy outcomes by reviewing inpatient records. Patients were categorized into an irAEs group and a non-irAEs group, with the former further subdivided into a multiple irAEs group and a single irAE group. Chi-square tests were employed to evaluate differences in baseline characteristics and efficacy outcomes between the irAEs and non-irAEs groups, as well as between the multiple and single irAE groups. Additionally, logistic regression analysis was utilized to identify risk factors linked to irAEs. RESULTS: Among 2523 eligible patients, 1096 reported 1802 irAEs, with an incidence incidence of 43.4%. Among 1096 individuals, 92.1% were classified as grade 1-2, while 7.9% were grade 3 or higher. IrAEs affected various organ systems, with endocrine toxicity (17.7%), hepatic toxicity (17.2%), and hematologic toxicity (11.4%) being the most common. 20.5% patients experienced multi-system irAEs. The average time for patients to develop irAEs was within four treatment cycles. Significant differences in patient gender, age, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), comorbidities, PD-1 or PD-L1 inhibitors, and treatment modalities were observed between the irAEs and non-irAEs groups, but not between the multiple irAEs and single irAE groups. Compared to the non-irAEs group, the irAEs group exhibited a higher objective response rate (ORR) and disease control rate (DCR), and the multiple irAEs group also showed a higher ORR than the single irAE group. CONCLUSION: This real-world study indicated that the occurrence of irAEs is related to patient gender, age, ECOG PS, comorbidities, PD-1/PD-L1 inhibitors, and treatment modalities. The occurrence of irAEs may be associated with better treatment benefits.
摘要：
α‑1 Antitrypsin (AAT) is an acute phase protein encoded by the serine protease inhibitor family A member 1 gene. This multifunctional protein serves several roles, including anti‑inflammatory, antibacterial, antiapoptotic and immune regulatory functions. The primary role of AAT is to protect tissues and organs from protease‑induced damage due to its function as a serine protease inhibitor. AAT is associated with the development of lung inflammation, liver inflammation and immune‑mediated inflammatory diseases, which are influenced by environmental and genetic factors. For instance, AAT acts as an anti‑inflammatory protein to prevent and reverse type I diabetes. The present study briefly reviewed the molecular properties and mechanisms of AAT, as well as advances in the study of lung, liver and inflammatory diseases associated with AAT. The potential of AAT as a diagnostic and therapeutic target for inflammatory and immune‑mediated inflammatory diseases was reviewed. In addition, the damaging and protective effects of AAT, and its effects on organ function were discussed.
摘要：
Cardiovascular diseases (CVDs), the leading cause of human death worldwide, are diseases that affect the heart and blood vessels and include arrhythmias, coronary atherosclerotic heart disease, hypertension, and so on. Resveratrol (RSV) is a natural nonflavonoid phenolic compound with antioxidant, anti-inflammatory, anticancer, and cardiovascular protection functions. RSV has shown significant protective effects against CVD. However, RSV's clinical application is limited by its tendency to be oxidized and metabolized easily. Therefore, it is necessary to optimize the RSV structure. This review will introduce the activity, synthesis, and structure-activity relationships of RSV derivatives, and the mechanism of the action of RSV in CVDs in recent years.
通讯机构：
[Yu, CY; Wei, H ] U;[Yu, CY ] Z;Zhejiang Univ, Dept Chem, Hangzhou 310027, Peoples R China.;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang 421001, Peoples R China.;Univ South China, Dept Pharm & Pharmacol, Hengyang 421001, Peoples R China.
关键词：
enzyme-responsive;GSH-responsive;cross-linked shells;unimolecular micelles;anticancer drug delivery
摘要：
Cross-linked polymeric micelles capable of undergoing de-cross-linking triggered by tumor microenvironment (TME) provide a solution to the extracellular stability vs intracellular destabilization dilemma of nanomedicine. Herein, we reported a simple yet effective strategy for the one-pot construction of enzyme and glutathione (GSH) dual-responsive zwitterionic copolymer micelles consisting of hydrophobic enzyme-degradable polytyrosine (PTyr) cores and cross-linked zwitterionic poly(oligo(ethylene glycol)monomethyl ether methacrylate- co -sulfobetaine methacrylate- co -disulfide dimethacrylate) ( P (OEGMA- co -SBMA- co -DSDMA)) shells. Notably, the development of unimolecular zwitterionic copolymer micelles could be achieved simultaneously in the polymer synthesis process via regulating the feed ratio of a functionalized monomer, DSDMA, as a cross-linker. The optimized polymer construct could form stable unimolecular micelles with a drug-loading content (DLC) of 14.9% and an entrapment efficiency (EE) of 87.7% for DOX, along with promoted in vitro drug release and tumor inhibition ratio (TIR). The simple synthetic strategy developed herein provides a widespread approach for the production of multifunctional cross-linked polymeric delivery systems for efficient anticancer drug transportation.
摘要：
Tannic acid (TA) is the primary bioactive component in the gallnut (Galla chinensis) and has exhibited the anticancer effects. However, the mechanism of its anti-cancer activity in nasopharyngeal carcinoma (NPC) remains unclear. This research aims to explore the underlying mechanism of TA in the treatment of nasopharyngeal cancer using network pharmacology, molecular docking and experimental validation. Firstly, the targets of TA and NPC were predicted and collected through databases, and the intersection targets were identified. Subsequently, protein-protein interaction (PPI) network analysis, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes Genomes (KEGG) pathway enrichment analysis, molecular docking and molecular dynamics (MD) simulation were conducted to uncover the potential mechanisms of TA in treatment of NPC. Finally, in vitro experiments were utilized to verify the mechanism of TA with anticancer activity in NPC. The results of network pharmacology revealed 42 intersection targets between NPC-related targets and TA-related targets. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was identified as the main target pathway of TA against NPC. Additionally, molecular docking and MD simulation confirmed the closely binding affinities of TA with AKT1. Furthermore, the results of in vitro experiments demonstrated that TA exerts anticancer activity against NPC by targeting the PI3K/AKT signaling pathway, leading to the suppression of cell proliferation. TA is a promising therapeutic candidate for NPC through PI3K/AKT signaling pathway. These results provide insights into the clinical application of TA, particularly when considered in combination with other therapeutic modalities.
摘要：
Detergents are essential for preserving the structural integrity and functionality of membrane proteins (MPs) outside the biological membrane or in aqueous solution, and thus ensuring accurate biochemical and structural analyses. Here, we introduce peptide-scaffolded detergents, a novel class of hybrid molecules formed by preassembling detergent monomers with peptides of varying lengths, mediated via Click chemistry. These detergents are characterized by scalable, straightforward synthesis and enhanced solubility. Among the variants, A4B2 emerged as the optimal detergent, demonstrating superior thermal stabilization across a range of G protein-coupled receptors, including A2AAR, SMO and GLP-1R. Additionally, A4B2 exhibits a low critical micelle concentration and small micelle size, together making it particularly effective for electron microscopy studies of A2AAR. This innovative design leverages the benefits of peptide-based and traditional detergents, offering new insights for the development of advanced detergents in MP research.
作者机构：
[Tang, Ya] School of Public Health, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, China;[Tang, Ya] Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China;[Hao, Bo; Hu, Haihong; Zhan, Wendi; Zhu, Hongxia] Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China;[Chen, Siyuan] Department of Breast and Thyroid Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China;[Xu, Xuefeng] Department of Function, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
摘要：
NAD(P)H dehydrogenase quinone 1 (NQO1) is overexpressed in various cancers and is strongly associated with an immunosuppressive microenvironment and poor prognosis. In this study, we explored the role of NQO1 in the microenvironment, prognosis and immunotherapy of Hepatocellular carcinoma (HCC) using multi-omics analysis and machine learning. The results revealed that NQO1 was significantly overexpressed in HCC cells. NQO1(+)HCC cells were correlated with poor prognosis and facilitated tumor-associated macrophages (TAMs) polarization to M2 macrophages. We identified core NQO1-related genes (NRGs) and developed the NRGs-related risk-scores in hepatocellular carcinoma (NRSHC). The comprehensive nomogram integrating NRSHC, age, and pathological tumor-node-metastasis (pTNM) Stage achieved an area under the curve (AUC) above 0.7, demonstrating its accuracy in predicting survival outcomes and immunotherapy responses of HCC patients. High-risk patients exhibited worse prognoses but greater sensitivity to immunotherapy. Additionally, a web-based prediction tool was designed to enhance clinical utility. In conclusion, NQO1 may play a critical role in M2 polarization and accelerates HCC progression. The NRSHC model and accompanying tools offer valuable insights for personalized HCC treatment.
期刊：
Drug Design, Development and Therapy,2025年19:239-250 ISSN：1177-8881
通讯作者：
Yan, P
作者机构：
[Lu, Hong; Yan, Pan; Zeng, Ying; Yan, P; Shi, Qun-Zhi; Gong, Yong-Qing; Liu, Lin] Univ South China, Affiliated Changsha Cent Hosp, Hengyang Med Sch, Dept Pharm, Changsha 410004, Peoples R China.;[Li, Sen] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430030, Peoples R China.
通讯机构：
[Yan, P ] U;Univ South China, Affiliated Changsha Cent Hosp, Hengyang Med Sch, Dept Pharm, Changsha 410004, Peoples R China.
关键词：
anti-tuberculosis drug-induced liver injury;automatic machine learning;children;gradient boost machine;retrospective study
摘要：
PURPOSE: Drug-induced liver injury (DILI) is one of the most common and serious adverse drug reactions related to first-line anti-tuberculosis drugs in pediatric tuberculosis patients. This study aims to develop an automatic machine learning (AutoML) model for predicting the risk of anti-tuberculosis drug-induced liver injury (ATB-DILI) in children. METHODS: A retrospective study was performed on the clinical data and therapeutic drug monitoring (TDM) results of children initially treated for tuberculosis at the affiliated Changsha Central Hospital of University of South China. After the features were screened by univariate risk factor analysis, AutoML technology was used to establish predictive models. The area under the receiver operating characteristic curve (AUC) was used to evaluate model's performance, and then the TreeShap algorithm was employed to interpret the variable contributions. RESULTS: A total of 184 children were enrolled in this study, of whom 19 (10.33%) developed ATB-DILI. Univariate analysis showed that seven variables were risk factors for ATB-DILI, including the plasma peak concentration (C(max)) of rifampicin, body mass index (BMI), alanine aminotransferase, total bilirubin, total bile acids, aspartate aminotransferase and creatinine. Among the numerous predictive models constructed by the "H2O" AutoML platform, the gradient boost machine (GBM) model exhibited the superior performance with AUCs of 0.838 and 0.784 on the training and testing sets, respectively. The TreeShap algorithm showed that C(max) of rifampicin and BMI were important features that affect the AutoML model's performance. CONCLUSION: The GBM model established by AutoML technology shows high predictive accuracy and interpretability for ATB-DILI in children. The prediction model can assist clinicians to implement timely interventions and mitigation strategies, and formulate personalized medication regimens, thereby minimizing potential harm to high-risk children of ATB-DILI.
作者机构：
[Yang, Xiaoyan; Yuan, Weixi; Long, Jianling; Tang, Guotao; Tang, GT; Ye, Pengju; Xie, Zhizhong; Deng, Xiangping; Lei, Xiaoyong; Deng, XP; Yang, Qixian] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm,Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.;[Wang, Zhe] Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;[Xiao, Hongxiang] Hunan Haopifu Pharmaceut Co Ltd, Changsha, Hunan, Peoples R China.
通讯机构：
[Tang, GT ; Deng, XP] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm,Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.
关键词：
Breast cancer;Estrogen receptor;Flavonoids;Structure-activity
摘要：
Breast cancer (BC) stands as the most prevalent malignancy among women. Targeting the estrogen receptor (ER) or ER pathway is one of the important approaches for ER + BC treatment. As a class of phytoestrogens, flavonoids possess notable anti-tumor properties and hold immense potential in regulating ER signaling. In this review, we reported the recent advances in both in vitro and in vivo studies of flavonoids and their synthetic derivatives targeting the ER signaling pathway, including the target and mechanism of action of these molecules, as well as their structure–activity relationship. Based on the available literature, the beneficial effects of flavonoids as ER targeting agents are promising but they require further in vitro and in vivo studies to enable its translation from bench to bedside. This review will provide valuable guidance and insights for the future development of drugs targeting the ER pathway.
Breast cancer (BC) stands as the most prevalent malignancy among women. Targeting the estrogen receptor (ER) or ER pathway is one of the important approaches for ER + BC treatment. As a class of phytoestrogens, flavonoids possess notable anti-tumor properties and hold immense potential in regulating ER signaling. In this review, we reported the recent advances in both in vitro and in vivo studies of flavonoids and their synthetic derivatives targeting the ER signaling pathway, including the target and mechanism of action of these molecules, as well as their structure–activity relationship. Based on the available literature, the beneficial effects of flavonoids as ER targeting agents are promising but they require further in vitro and in vivo studies to enable its translation from bench to bedside. This review will provide valuable guidance and insights for the future development of drugs targeting the ER pathway.
