查找使用阿拉丁产品的科研文献

Nuclear-targeted p53 and DOX co-delivery of chitosan derivatives for cancer therapy in vitro and in vivo

Jian-Tao Lin,Hua Chen,Dan Wang,Liang Xiong,Jia-Zhu Li,Gui-hong Chen,Guang-Bin Chen

The nucleus is one of the most important cellular organelles. Chitosan-grafted poly-(N-3-carbobenzyloxy-lysine) (CCL) decorated with human immunodeficiency virus-1 transactivator of transcription (TAT) can co-deliver p53 and doxorubicin into the nucleus simultaneously, such that their antitumor functions are exerted. However, TAT-CCL has been shown to have an anti-tumor effect only in vitro; the effect in vivo was unsatisfactory. Here, a unique nucleus-targeted delivery system based on amidized TAT (aTAT)-CCL with aTAT functional on the surface was designed to achieve a highly efficient nucleus-targeting gene and drug delivery system for effective cancer cell elimination in vitro and in vivo. In this delivery system, TAT is amidized to inhibit its nonspecific interactions. Confocal laser scanning microscopy observations revealed that if aTAT-CCL was incubated in pH 5.0 acetate buffer solution for 24 h before use (named aTAT-CCL-HB), more aTAT-CCL-HB entered the nucleus compared with aTAT-CCL or CCL. aTAT-CCL-HB can also achieve high gene transfection and drug delivery efficiencies and low viability in HepG2 cells. However, only aTAT-CCL achieved extensive circulation in the blood compartment and high antitumor activity in vivo. Amidization of TAT in vectors may become a promising strategy for nucleus-targeted delivery systems, especially in in vivo applications.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer

Longkun Wang,Chunqian Zhao,Lu Lu,Honglei Jiang,Fengshan Wang,Xinke Zhang

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.Keywords:paclitaxel;peptide-drug conjugate;TAT peptide;A7R peptide;targeted delivery;anticancer therapy;transcytosis

Investigation of Dual-Loaded Doxorubicin and Sorafenib Liposomes Co-Modified with Glycyrrhetinic Acid and Cell-Penetrating Peptide TAT

Houlin Su,Zhiqiang Tu,Lin Jing,Yanling Huang,Xu Liu,Mingqing Yuan

BackgroundCombining Doxorubicin (DOX) with sorafenib (SF) is a promising strategy for treating Hepatocellular Carcinoma (HCC). However, strict dosage control is required for both drugs, and there is a lack of target selectivity.ObjectiveThis study aims to develop a novel nano-drug delivery system for the combined use of DOX and SF, aiming to reduce their respective dosages, enhance therapeutic efficacy, and improve target selectivity.MethodsDOX/SF co-loaded liposomes (LPs) were prepared using the thin-film hydration method. The liposomes were modified with 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE)-polyethylene glycol (PEG2000), DSPE-PEG1000-cell penetrating peptide TAT, and Glycyrrhetinic Acid (GA). The basic properties of the liposomes were characterized. CCK-8 cell viability assays were conducted using HepG2, MHCC97-H, and PLC cell models, and apoptosis experiments were performed using HepG2 cells to determine if this delivery system could reduce the respective dosages of DOX and SF and enhance HCC cytotoxicity. Liposome uptake experiments were performed using HepG2 cells to validate the target selectivity of this delivery system.ResultsA GA/TAT-DOX/SF-LP liposomal nano drug delivery system was successfully constructed, with a particle size of 150 nm, a zeta potential of -7.9 mV, a DOX encapsulation efficiency of 92%, and an SF encapsulation efficiency of 88.7%. Cellular experiments demonstrated that this delivery system reduced the required dosages of DOX and SF, exhibited stronger cytotoxicity against liver cancer cells, and showed better target selectivity.ConclusionA simple and referenceable liposomal nano drug delivery system has been developed for the combined application of DOX and SF in hepatocellular carcinoma treatment.

Targeted degradation of hexokinase 2 for anti‑inflammatory treatment in acute lung injury

Jiayan Yang,Liangliang Dong,Yifan Wang,Lifen Gong,Hongwei Gao,Yicheng Xie

Acute lung injury (ALI) is an acute inflammatory lung disease associated with both innate and adaptive immune responses. Hexokinase 2 (HK2) is specifically highly expressed in numerous types of inflammation‑related diseases and models. In the present study in vitro and in vivo effects of targeted degradation of HK2 on ALI were explored. The degradation of HK2 by the targeting peptide TAT (transactivator of transcription protein of HIV‑1)‑ataxin 1 (ATXN1)‑chaperone‑mediated autophagy‑targeting motif (CTM) was demonstrated by ELISA and western blotting in vitro and in vivo. The inhibitory effects of TAT‑ATXN1‑CTM on lipopolysaccharide (LPS)‑induced inflammatory responses were examined using ELISAs. The therapeutic effects of TAT‑ATXN1‑CTM on LPS‑induced ALI were examined via histological examination and ELISAs in mice. 10 µM TAT‑ATXN1‑CTM administration decreased HK2 protein expression and the secretion of proinflammatory cytokines (TNF‑α and IL‑1β) without altering HK2 mRNA expression in LPS‑treated both in vitro and in vivo, while pathological lung tissue damage and the accumulation of leukocytes, neutrophils, macrophages and lymphocytes in ALI were also significantly suppressed by 10 µM TAT‑ATXN1‑CTM treatment. TAT‑ATXN1‑CTM exhibited anti‑inflammatory activity in vitro and decreased the severity of ALI in vivo. HK2 degradation may represent a novel therapeutic approach for ALI.

Membrane-Active All-Hydrocarbon-Stapled α-Helical Amphiphilic Tat Peptides: Broad-Spectrum Antibacterial Activity and Low Incidence of Drug Resistance

Shu Li,Zhaopeng Wang,Shibo Song,Yuanyuan Tang,Jingjing Zhou,Xiaojing Liu,Xingjiao Zhang,Min Chang,Kairong Wang,Yali Peng

Multidrug resistance against conventional antibiotics has dramatically increased the difficulty of treatment and accelerated the need for novel antibacterial agents. The peptide Tat (47–57) is derived from the transactivating transcriptional activator of human immunodeficiency virus 1, which is well-known as a cell-penetrating peptide in mammalian cells. However, it is also reported that the Tat peptide (47–57) has antifungal activity. In this study, a series of membrane-active hydrocarbon-stapled α-helical amphiphilic peptides were synthesized and evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The impact of hydrocarbon staple, the position of aromatic amino acid residue in the hydrophobic face, the various types of aromatic amino acids, and the hydrophobicity on bioactivity were also investigated and discussed in this study. Among those synthesized peptides, analogues P3 and P10 bearing a l-2-naphthylalanine (Φ) residue at the first position and a Tyr residue at the eighth position demonstrated the highest antimicrobial activity and negligible hemolytic toxicity. Notably, P3 and P10 showed obviously enhanced antimicrobial activity against multidrug-resistant bacteria, low drug resistance, high cell selectivity, extended half-life in plasma, and excellent performance against biofilm. The antibacterial mechanisms of P3 and P10 were also preliminarily investigated in this effort. In conclusion, P3 and P10 are promising antimicrobial alternatives for the treatment of the antimicrobial-resistance crisis.

RGD/TAT-functionalized chitosan-graft-PEI-PEG gene nanovector for sustained delivery of NT-3 for potential application in neural regeneration

Dongni Wu,Yongnu Zhang,Xiaoting Xu,Ting Guo,Deming Xie,Rong Zhu,Shengfeng Chen,Seeram Ramakrishna,Liumin He

In this study, we prepared a multifunctional gene delivery nanovector containing a chitosan (CS) backbone and polyethylenimine (PEI) arms with arginine-glycine-aspartate (RGD)/twin-arginine translocation (TAT) conjugated via polyethylene glycol (PEG). Branched PEI, with a molecular weight of 2000 Da, was used to achieve a balance between biocompatibility and transfection efficiency, whereas RGD/TAT peptides were conjugated for enhanced targeting ability and cellular uptake. Synthesis of the copolymers was confirmed by characterizing the chemical structure with 1 H nuclear magnetic resonance and Fourier Transform Infrared Spectroscopy (FTIR). The nanovector was biocompatible with cells and showed excellent capability for DNA condensation ; the resulting complexes with DNA were well-formed, and possessed small particle size and reasonable positive charge. Higher gene transfection efficiency, compared to that achieved with PEI (25 kDa), was confirmed in tumor (HeLa cells) and normal cells (293T and NIH 3T3 cells). More importantly, the cells transfected with the chitosan- graft -PEI-PEG/pCMV-EGFP-Ntf3 complex produced sustained neurotrophin-3 with a linear increase in cumulative concentration, which induced neuronal differentiation of neural stem cell and promoted neurite outgrowth . These findings suggested that our multifunctional copolymers might be ideal nanovectors for engineering cells via gene transfection, and could potentially be applied in tumor therapy and regenerative medicine. Statement of Significance We successfully prepared a multifunctional gene delivery nanovector containing branched PEI with a molecular weight of 2000 Da to balance between biocompatibility and transfection efficiency, and RGD/TAT peptides for enhanced targeting ability and cellular uptake. The well-formed CPPP/DNA complexes of small particle size and reasonable positive charges potentially enhanced gene transfection in both tumor and normal cells. More importantly, the CPPP/pCMV-EGFP-Ntf3 complex-transfected 293T cells could produce sustained NT-3 with a constant ratio, which induced neuron differentiation of NSC and promoted neurite outgrowth. Therefore, our study provided an effective strategy for producing neurotrophins by engineering cells with gene delivery, which deserved wide investigation and potential application in regenerative medicine.

Scoparone enhances the stability of TAT protein by inhibiting the Ubiquitin-Proteasome pathway, regulates mitochondrial damage againest chronic alcoholic liver disease

Chaozhong Wang,Yuran Sun,Le Yang,Junling Ren,Heng Fang,Ye Sun,Guangli Yan,Ling Kong,Ying Han,Xijun Wang,Hui Sun

Ethnopharmacological relevance Artemisia capillaris Thunb. is a traditional Chinese medicinal herb commonly used in clinical practice for chronic alcoholic liver disease (CALD).Scoparone, one of the major active components of Artemisia capillaris Thunb., has emerged as a promising candidate for CALD intervention, yet its mechanism remains unclear. Aim of the study This study aimed to systematically elucidate the pharmacological effects of scoparone and its molecular mechanisms in CALD via multi-omics combined with targeted validation. Materials and methods The National Institute on Alcohol Abuse and Alcoholism (NIAAA) animal model was established. The NIAAA-established CALD mouse model (chronic ethanol feeding + acute binge, mimicking acute-on-chronic liver injury) was diagnosed via classic clinical methods (liver function biomarkers + histopathology). After validation, scoparone exhibited significant efficacy across different doses. Metabolomics and transcriptomics analyzed urine/tissue samples, with integrated analysis identifying core hubs. Meanwhile, primary hepatocytes were cultured and treated with scoparone. Potential targets were validated via gene knockdown, CETSA, CHX chase, and ubiquitination assays. We used the Seahorse XF Mito Stress Test to evaluate CALD-associated mitochondrial damage and elucidate the key interrelationships. Results Scoparone normalized serum biochemical indices and liver pathology to near-healthy levels. Urinary metabolomics identified 9 biomarkers, and liver transcriptomics detected 3665 differentially expressed genes.Integrated omics pinpointed the phenylalanine pathway, with TAT/AST co-regulation identified as key. In vitro, primary hepatocytes were cultured with 100 mmol/L ethanol ±25 μmol/L scoparone; CETSA and CHX chase assays confirmed scoparone enhances TAT stability via inhibiting the Ubiquitin-Proteasome pathway. Seahorse analysis showed TAT knockdown-induced hepatocyte apoptosis, oxidative stress, lipid accumulation, and mitochondrial damage were reversed by scoparone or TAT level restoration. Conclusions This study first reveals scoparone’s novel mechanism in treating CALD: it directly binds tyrosine aminotransferase (TAT), stabilizes its level by inhibiting Ubiquitin-Proteasome-mediated degradation, restores TAT’s regulation of phenylalanine to prevent tyrosinemia and associated liver injury or jaundice, and normalizes tyrosine regulation to recover mitochondrial tricarboxylic acid cycle-related pyruvate, reversing oxidative stress and mitochondrial dysfunction.This study validates scoparone as a potential CALD therapeutic and provides robust preclinical data for TAT-targeted therapy.

Efficient separation of radium from natural thorium using a mesoporous silica-supported composite resin with sulfonic acid groups for the acquisition of targeted α-nuclides 212Pb

Jing Tang,Linyuan Liao,Xuexiang He,Lidan Lv,Xiangbiao Yin,Wenlong Li,Yuezhou Wei,Shunyan Ning,Lifeng Chen

212 Pb serves as one of the most important nuclides for targeted alpha therapy (TAT), with good potential in the treatment of malignant tumors. However, medical and clinical applications are seriously limited by its extremely short supply, which strongly depends on the acquisition of its parent nuclides such as 228 Ra or 224 Ra. To address this issue, we conducted a systematic investigation on the separation of trace radium from natural thorium using the ion exchange chromatography method, and a novel porous silica-based composite resin functionalized with sulfonic acid groups was prepared, characterized, and employed. Experimental results showed that the silica-supported resin was successfully prepared with the sulfonic acid groups, and possessed small particle size, mesoporous pore structure and large specific surface area. The resin exhibited high selectivity toward thorium compared with barium, and the separation factor reached 123 at low acidity and at low temperature. The resin demonstrated a fast adsorption speed and an excellent separation performance, and the adsorption mechanism was confirmed based on the ion exchange between the sodium carried and the target cations. On the basis, column experiments were further conducted and finally the separation of trace radium from thorium was realized using a small column filled with about 1.0 g resin. The chemical recovery of radium reached 97 %, and the decontamination factor for thorium exceeded 40,000. This work verifies the feasibility of directly extracting 228 Ra and 224 Ra from natural thorium using the sulfonic acid group functionalized materials in the dilute nitric acid solution, and presents an excellent material and systematic experimental data on the separation activities, rendering this study particularly significant.

Co-delivery of siPD-L1 and Tat-HSPB1 by G5PBA Enhances the Efficacy of Antitumor Therapy in Clear Cell Renal Cell Carcinoma

Kui Xiong,Lili Xia,Lin Zhang,Weiyuan Li,Yan An,Xiangyang Shi,Guang-Zhi Jin

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and remains challenging to treat at advanced stages due to immune evasion and inefficient intracellular delivery of therapeutic agents. In this study, we synthesized a modified generation 5 (G5) poly(amidoamine) dendrimer (G5PBA) to co-deliver small-interfering RNA targeting programmed death-ligand 1 (siPD-L1) and the antitumor peptide Tat-HSPB1, forming the G5PBA/siPD-L1/Tat-HSPB1 nanocomplex. The agarose gel retardation assay demonstrated that G5PBA efficiently condensed siPD-L1. Furthermore, the peptide encapsulation efficiency and loading capacity were measured, confirming the loading of Tat-HSPB1 into G5PBA/siPD-L1. Flow cytometry showed that G5PBA enhanced the cellular uptake of siPD-L1, while confocal microscopy demonstrated that G5PBA promoted lysosomal escape in Caki-1 cells. Western blot analysis further confirmed that G5PBA effectively reduced the PD-L1 protein expression. In cellular experiments, CCK-8, EdU, and wound-healing assays demonstrated that G5PBA/siPD-L1/Tat-HSPB1 inhibited the viability and migration of ccRCC cells. G5PBA/siPD-L1/Tat-HSPB1 suppressed tumor growth, downregulated PD-L1 expression, enhanced CD4+ and CD8+ T-cell infiltration, and elevated serum levels of IL-2, IL-6, TNF-α, and IFN-γ in mice. Major organs exhibited no obvious histopathological abnormalities upon H&E staining. Serum ALT, AST, and BUN levels showed no significant changes compared with the PBS group, suggesting the preliminary safety profile of G5PBA/siPD-L1/Tat-HSPB1. Collectively, the nanocomplex achieved efficient peptide/siPD-L1 co-delivery and demonstrated significant antitumor activity. This system thus provides a promising strategy and experimental basis for local administration of ccRCC.

Recent progress of mechanism of mineralization process induced by Ta2O5/PCL scaffolds

Chen Gao,Junbo Jiang,Juan Wang,Yutong Wang,Yangyang Zhang,Caihua Rao,Yue Cheng,Zhongrong Chen,Runhuai Yang,Gang Zhao

Mineralization of hydroxyapatite mineralized by acidic metal oxides has attracted substantial research interest in the research and development of orthopedic substitutes. In this study, Polycaprolactone (PCL) nanofibers with nano-tantalum oxide (Ta 2 O 5 ) were successfully fabricated through electrospinning. The scaffold simulates the mineralization process of hydroxyapatite in simulated body fluid. However, in the process of mineralization, there is a chemical reaction between hydrophobic scaffolds and acid oxides, which is believed to have a significant impact on the biological effects of the scaffolds. The results of SEM, EDS, XRD, Mapping, FTIR, GPC, 13 CNMR, and 1 HNMR explain the principle of hydroxyapatite mineralization by Ta 2 O 5 and the reason why the composite scaffold is blurred, that is, the carbonyl carbon of PCL attacked by the surface hydroxyl groups of Ta 2 O 5 to catalyze its ring-opening polymerization to synthesize PCL/Ta 2 O 5 nanocomposites in one step. In order to accurately explore the effect of this reaction on the metabolism of biological macromolecules in the future, we provide a detailed route of Ag Nanoparticles -Dimercaptosuccinic acid@Transcription activator (AgNPs-DMSA@TAT) probe synthesis. The results provide a reference for the sedimentation of hydroxyapatite induced by acid oxides and its effect on traditional electrospun fiber scaffolds.

Behaviour of cell penetrating peptide TAT-modified liposomes loaded with salvianolic acid B on the migration, proliferation, and survival of human skin fibroblasts

Jun Shi,Siyi Guo,Yanting Wu,Guitian Chen,Jianhui Lai,Xiaoqi Xu

Combining autophagy-inducing peptides and brefeldin A delivered by perinuclear-localized mesoporous silica nanoparticles: a manipulation strategy for ER-phagy

Yimin Wang,Zhao Zhao,Fujing Wei,Zewei Luo,Yixiang Duan

Autophagic degradation of the endoplasmic reticulum (ER-phagy) has been found to play a critical role in human sensory neuropathy. So far, however, specific and efficient intervention means for ER-phagy remain unexplored. Herein, brefeldin A (BFA), a blocking agent on protein transport between the ER and Golgi, was screened from ER stress inducers. BFA was then delivered to the perinuclear area co-localized with the ER by a mesoporous silica nanoparticle-based drug-carrier functionalized with autophagy-inducing peptides of TAT-beclin 1 (MSNs-BFA), to evoke a perturbation of ER-phagy. The molecular mechanism of ER-phagy regulated by BFA was explored by biochemical evaluation including time-lapse live-cell fluorescence imaging. We found that MSNs-BFA treatment caused a lower mRNA/protein expression level of FAM134b even under a compensation of autophagic flux in U2OS cells, and resulted in ER-expansion. The fragmentation of the ER was blocked as a response to ER stress mediated by inactivation of the AKT/TSC/mTOR pathway. Our work developed an efficient external manipulation strategy to regulate ER-phagy and may contribute to the therapeutic application of autophagy-related major human diseases.