WORLD JOURNAL OF GASTROENTEROLOGY
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2023
·
IF 4.3
Heng Shi,Xin-Hai Zhao,Qin Peng,Xian-Ling Zhou,Si-Si Liu,Chuan-Chuan Sun,Qiu-Yu Cao,Shi-Ping Zhu,Sheng-Yun Sun
BACKGROUND Di (2-ethylhexyl) phthalate (DEHP) is a common plasticizer known to cause liver injury. Green tea is reported to exert therapeutic effects on heavy metal exposure-induced organ damage. However, limited studies have examined the therapeutic effects of green tea polyphenols (GTPs) on DEHP-induced liver damage. AIM To evaluate the molecular mechanism underlying the therapeutic effects of GTPs on DEHP-induced liver damage. METHODS C57BL/6J mice were divided into the following five groups: Control, model [DEHP (1500 mg/kg bodyweight)], treatment [DEHP (1500 mg/kg bodyweight) + GTP (70 mg/kg bodyweight), oil, and GTP (70 mg/kg bodyweight)] groups. After 8 wk, the liver function, blood lipid profile, and liver histopathology were examined. Differentially expressed micro RNAs (miRNAs) and mRNAs in the liver tissues were examined using high-throughput sequencing. Additionally, functional enrichment analysis and immune infiltration prediction were performed. The miRNA-mRNA regulatory axis was elucidated using the starBase database. Protein expression was evaluated using immunohistochemistry. RESULTS GTPs alleviated DHEP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, liver fibrosis, and mitochondrial and endoplasmic reticulum lesions in mice. The infiltration of macrophages, mast cells, and natural killer cells varied between the model and treatment groups. mmu-miR-141-3p (a differentially expressed miRNA), Zcchc24 (a differentially expressed mRNA), and Zcchc24 (a differentially expressed protein) constituted the miRNA-mRNA-protein regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage in mice. CONCLUSION This study demonstrated that GTPs mitigate DEHP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, and partial liver fibrosis, and regulate immune cell infiltration. Additionally, an important miRNA-mRNA-protein molecular regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage was elucidated.
研究领域:
毒理学
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药理学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
Nanomaterials
·
2023
·Vol. 13
·期 11
·1779
·
IF 5.3
Shunyu Zhang,Jinxia Li,Liang Yan,Yue You,Feng Zhao,Jixing Cheng,Limin Yang,Yanqi Sun,Qingchao Chang,Ru Liu,Yunhui Li
Telomerase is constitutively overexpressed in the majority of human cancers and telomerase inhibition provides a promising broad-spectrum anticancer therapeutic strategy. BIBR 1532 is a well-known synthetic telomerase inhibitor that blocks the enzymatic activity of hTERT, the catalytic subunit of telomerase. However, water insolubility of BIBR 1532 leads to low cellular uptake and inadequate delivery and thus, limits its anti-tumor effects. Zeolitic imidazolate framework-8 (ZIF-8) is considered as an attractive drug delivery vehicle for improved transport, release and anti-tumor effects of BIBR 1532. Herein, ZIF-8 and BIBR[email protected]were synthesized, respectively, and the physicochemical characterizations confirmed the successful encapsulation of BIBR 1532 in ZIF-8 coupled with an improved stability of BIBR 1532. ZIF-8 could alter the permeability of lysosomal membrane probably by the imidazole ring-dependent protonation. Moreover, ZIF-8 encapsulation facilitated the cellular uptake and release of BIBR 1532 with more accumulation in the nucleus. BIBR 1532 encapsulation with ZIF-8 triggered a more obvious growth inhibition of cancer cells as compared with free BIBR 1532. A more potent inhibition on hTERT mRNA expression, aggravated G0/G1 arrest accompanied with an increased cellular senescence were detected in BIBR[email protected]cancer cells. Our work has provided preliminary information on improving the transport, release and efficacy of water-insoluble small molecule drugs by using ZIF-8 as a delivery vehicle.Keywords:ZIF-8;drug loading;transport;protonation effect;telomerase inhibitor
研究领域:
药学
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癌症研究
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药物递送系统
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分子生物学
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DOI
PubMed
高影响因子
Nanoscale
·
2021
·Vol. 14
·期 5
·1733-1741
·
IF 7.79
Tingting Zhao,Fengqi Dong,Xinlong Hu,Yanli Xu,Wenmei Wei,Rui Liu,Fang Yu,Weijun Fang,Yuxian Shen,Zhongping Zhang
Monitoring the expression level of the intracellular tumor suppressor gene p21 mRNA is essential to reveal the progress and prognosis of a tumor. Methods widely reported for the detection of p21 mRNA are the real-time polymerase chain reaction and Northern blot. However, these methods only detect mRNA in vitro and cannot realize the in situ monitoring of the p21 mRNA expression level in living cells. Additionally, the sensor for the real-time tracking and monitoring of the p21 mRNA location without the help of a transfection reagent in living cells is still limited. Herein, a novel sticky-flare was constructed for the dynamic monitoring of the temporal and spatial variations of p21 mRNA in living cells. The nanoprobe consists of AuNP, a recognition sequence modified with Cy5, and a thiol-modified DNA sequence. The thiol oligonucleotide strand could act partially complementary to the Cy5-modified oligonucleotide strand to form a double-stranded DNA linked to AuNP, resulting in the fluorescence quenching of Cy5 due to the energy transfer from Cy5 to the gold sphere. In the presence of p21 mRNA, the Cy5-modified recognition nucleic acid specifically bound to p21 mRNA to form a more stable double chain and escaped from the gold sphere, leading to the recovery of red fluorescence. Our method is better than other methods in its ability to quantify the spatial distribution and expression level of p21 mRNA in living cells and discriminate various tumor cell lines with different p21 mRNA expression levels by the naked eye. Particularly, the sticky-flare probe used in this assay could allow the visual evaluation of the tumor treatment effect and the determination of the tumor progression stage by enabling monitoring of the relative expression level of p21 mRNA in tumor cells after cisplatin treatment. The method reported here is accurate, reliable and needs no auxiliary tools (transfection reagent), and thereby provides a promising route for the prognostic evaluation and drug development of cancer treatment in the future.
研究领域:
癌症生物学
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分子生物学
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
CELLULAR ONCOLOGY
·
2026
·Vol. 49
·期 4
·94
·
IF 5.6
Wang Benlin,Zheng Xianchong,Hua Qingsheng,Zou Feng,Huang Tao,Chen Jiawei
Background Cisplatin-based chemotherapy is first-line for muscle-invasive bladder cancer (BLCA), but chemoresistance remains the primary barrier to clinical efficacy. RNA-binding proteins (RBPs) orchestrate post-transcriptional gene regulation and are increasingly implicated in cancer chemoresistance; however, the role and regulatory mechanism of the splicing factor RBP SLU7 in BLCA cisplatin resistance remain completely unknown. Methods We analyzed SLU7 expression and clinical prognosis in two independent cisplatin-treated BLCA cohorts (GSE87304, GSE169455). Cisplatin-resistant BLCA cell lines (T24-CIS, UMUC3-CIS) were established for functional assays (CCK-8, qRT-PCR, western blotting). Molecular interactions were validated by RIP-qPCR, immunofluorescence(IF), RNA-FISH, nucleocytoplasmic fractionation, co-immunoprecipitation (co-IP), and mass spectrometry (MS). In vivo therapeutic efficacy was assessed in BLCA xenograft models. Results SLU7 was significantly upregulated in cisplatin-resistant BLCA cells, and high SLU7 expression independently predicted poor cancer-specific survival (CSS) and recurrence-free survival (RFS) in cisplatin-treated patients. SLU7 knockdown suppressed MAP3K3 expression, inhibited p38 MAPK pathway, and restored cisplatin sensitivity. Mechanistically, SLU7 directly bound MAP3K3 mRNA and promoted its nuclear export—a non-canonical function independent of its canonical splicing activity. MS and Co-IP identified NAA50 as the upstream regulator that catalyzes N-terminal acetylation of SLU7 to prevent its ubiquitin-proteasomal degradation, thereby sustaining SLU7 stability. Pharmacological inhibition of NAA50 with Naa50-IN-1 destabilized SLU7, blocked the MAP3K3-p38 axis, and reversed cisplatin resistance in vitro and in vivo. Conclusions We uncover a novel NAA50–SLU7–MAP3K3-p38 MAPK regulatory axis that drives cisplatin resistance in BLCA. NAA50-mediated N-terminal acetylation stabilizes SLU7, which in turn facilitates MAP3K3 mRNA nuclear export to activate p38 MAPK signaling. Targeting NAA50 represents a promising therapeutic strategy to overcome cisplatin resistance in BLCA, and SLU7 serves as a predictive biomarker for cisplatin response.
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高影响因子
ADVANCED MATERIALS
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2026
·
IF 29.1
Qiu Wang,Yi Lin,Jiahui Xiao,Keqing Xu,Zijin Luo,Hongyu Ren,Fan Liu,Lu Jia,Tuo Wei,Qiang Cheng
Highly efficient mRNA lipid nanoparticle (LNP) often presents potential safety risks. Here, we establish a structure–activity relationship framework for peptide ionizable lipids (PILs) to facilitate the rational design of safe and effective mRNA-LNPs. The PIL structure comprises three modular components: building block, side-chain length, and hydrophobic tail. Through systematic optimization, a lead compound (Dab4) with four building blocks and a moderate side chain length was identified, demonstrating minimized hepatotoxicity while maintaining superior delivery performance. Leveraging this framework, a series of Dab4-derived PILs with three tail types, including alkyl (a-tail), ester (aat-tail), and hydroxyl (e-tail), were synthesized. This tail chemistry determined organ tropism, with B12-a13Dab4 (a-tail) showing optimal performance in the liver. The B12-a13Dab4 LNP exhibited significantly higher hepatic delivery efficiency and markedly improved biosafety compared with the FDA-approved SM-102 formulation. Moreover, B12-a13Dab4 LNP efficiently triggers in vivo prime editing by co-delivering PE7 mRNA and epegRNA, and achieves significant therapeutic effects in a Hereditary Tyrosinemia Type 1 (HT-1) model through repeated delivery fumarylacetoacetate hydrolase (FAH) mRNA. This study establishes rational design principles for PILs that strike a balance between efficacy and safety, offering a versatile mRNA-LNP platform for the advancement of gene editing and protein replacement therapies.
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DOI
PubMed
高影响因子
iScience
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2026
·Vol. 29
·期 10
·117519
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IF 4.5
Ziqi Wen,Yiling Long,Wenjing Shi,Wenjing Song,Rongjun Xu,Xingri Zhan,Xiuyuan Wang,Rui Su,Yu Wang,Jia Fei
PAH sa-mRNA-LNP enables sustained PAH expression in vitro and in vivo • PAH sa-mRNA-LNP achieves efficacy at one-sixth the dose of nr-mRNA-LNP • A single PAH sa-mRNA-LNP dose maintains physiological Phe levels in Pah-KO mice • Repeated PAH sa-mRNA-LNP dosing shows favorable tolerability in Pah-KO mice Summary Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficient phenylalanine hydroxylase (PAH) activity, with current pharmacotherapies showing limited response rates and age-dependent restrictions. We compared two liver-targeted lipid nanoparticle formulations delivering PAH-encoding mRNA—a self-amplifying construct (saRNA) and a conventional non-replicating counterpart (nr-mRNA)—in Pah-knockout mice. Both constructs reduced circulating phenylalanine (Phe) after a single intravenous injection. The saRNA formulation achieved comparable efficacy at one-sixth the nr-mRNA dose and maintained physiological Phe levels for 14 days, whereas nr-mRNA produced only transient reductions. Repeated saRNA administration was well tolerated, with no detectable immunogenicity or hepatic toxicity. These results establish that saRNA-mediated PAH replacement provides sustained activity with substantial dose reduction, overcoming the short-lived effect of non-replicating mRNA. This platform may inform broader strategies for durable enzyme therapy in inherited metabolic diseases requiring liver-restored function. Download: Download high-res image (147KB) Download: Download full-size image
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高影响因子
FISH & SHELLFISH IMMUNOLOGY
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2026
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IF 4.2
Yao Zhang,Xizheng Zhang,Huiqing Chen,Weijun Mai
Developed a thermostable flaA mRNA-LNP vaccine against V. harveyi for large yellow croaker. • Stable at 25 °C for 10 weeks; eliminates cold-chain dependence. • High capping efficiency and antigen expression ensure strong immunogenicity in fish. • Elicits robust humoral and cellular immunity via the TLR5/MyD88 pathway. • Most effective dose among those evaluated: 20 μg, yielding 77.7% survival and 70.1% RPS. Vibrio harveyi causes severe vibriosis in the large yellow croaker ( Larimichthys crocea ), resulting in high mortality rates and significant economic losses in mariculture. Currently, there is no effective commercial vaccine available, and the overuse of antibiotics raises concerns about resistance and the environment. In this study, we developed a thermostable mRNA-LNP vaccine that encodes the FlaA flagellin, which is a key virulence and immunogenic antigen of V. harveyi . Through the optimisation of UTRs, capping, lipid nanoparticle (LNP) formulation, microfluidic encapsulation and lyophilisation, the vaccine achieved a capping efficiency of 95.1% and retained over 50% of the mRNA in kidney cells 12 h after transfection. The lyophilised vaccine remained stable with respect to physicochemical parameters and in vitro antigenicity at 25 °C for 10 wk, and retained the ability to induce neutralising antibodies. Intramuscular injection of the vaccine into croakers resulted in robust FlaA expression in muscle tissue, elevated levels of specific IgM and neutralising antibodies, increased antioxidant and metabolic enzyme activities, and expression of immune-related genes in immune tissues. A V. harveyi challenge demonstrated that a 20 μg dose was the most effective among the tested doses, with 77.7% survival and 70.1% relative percent survival. This is the first room-temperature-stable mRNA-LNP vaccine against an aquatic bacterial pathogen, offering a novel, eco-friendly strategy for controlling V. harveyi and advancing the development of mRNA vaccines for bacterial diseases in aquaculture.
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DOI
PubMed
高影响因子
Nano Today
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2026
·
IF 10.7
Jingjiao Li,Mingjia Wu,Jia Dong,Xuanxuan Li,Sujia Liu,Ge Mu,Xuefeng Duan,Jiaqi Lin,Xueguang Lu,Yuhai Bi
Seasonal influenza causes a significant global disease burden every year. Currently licensed injectable influenza vaccines mainly elicit humoral immune responses with minimal mucosal immunity in the respiratory tract, limiting their ability to block viral infection and transmission. Messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) offer rapid design and flexibility and are highly immunogenic, yet share this limitation of mucosal immunity. Here, we developed influenza A and B mRNA vaccines (Am80-LNP/IFA and Am80-LNP/IFB) using Am80-loaded LNP (Am80-LNP) encoding viral hemagglutinin (HA). Intramuscular immunization of mice with Am80-LNP/IFB (encoding influenza B/Victoria HA) at 1 and 10 μg doses induced systemic HA-specific IgG responses comparable to those elicited by a commercial LNP formulation (SM102-LNP/IFB) and a licensed split vaccine. Notably, Am80-LNP/IFB markedly enhanced respiratory mucosal immunity, inducing 5.4-fold (1 μg) and 11.8 -fold (10 μg) higher virus-specific IgA in bronchoalveolar lavage fluid relative to SM102-LNP. In addition, Am80-LNP/IFB-10 increased lung CD4⁺ tissue-resident memory T (T RM ) cells by 1.4-fold. Following lethal challenge of the influenza B virus, all mRNA-LNP/IFB vaccinated mice survived without weight loss, whereas the split-vaccinated mice experienced a transient decline to 88% of their initial body weight. Am80-LNP/IFB significantly reduced viral loads, rendering viral RNA undetectable in the lungs and nasal turbinates by 14 days post-infection (dpi) at a 10 μg dose. In addition, the Am80-LNP/IFA vaccine (encoding A/H1N1 HA) achieved complete viral clearance in nasal turbinates by 3 dpi, outperforming the split vaccine. These findings indicate that Am80-LNP enables injectable influenza mRNA vaccines to induce robust systemic immunity together with potent respiratory mucosal IgA and T RM responses, overcoming a major limitation of current inactivated vaccines.
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DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
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IF 13.2
Yu Han,Xintao Gao,Jiqing Dong,Mingquan Jiang,Ning Xin,Xiangyan Chen,Zhibo Li,Yantao Li
The clinical translation of mRNA vaccines for cancer immunotherapy critically hinges on the development of mRNA nanocarriers that ensure precise organ targeting, potent immune activation, and high biosafety. Here, we reported the novel supramolecularly engineered mRNA nanocarriers based on Zn 2+ -lipid nanoparticle (LNP) coordinated nanoassemblies (NAs), incorporating imidazole-functionalized ionizable lipids and Zn 2+ ions as structural and immunostimulatory components. Specifically, a library of 32 imidazole-based ionizable lipids was synthesized and screened, identifying BR5–2 LNPs as a lead candidate for efficient mRNA transfection. By leveraging the coordination interaction between Zn 2+ and the components of BR5–2 LNPs, we successfully constructed Zn-BR5–2 NAs, which exhibited enhanced in vitro mRNA transfection efficiency and promoted dendritic cell maturation via upregulation of major histocompatibility complex class I (MHC-I) antigen presentation. In vivo , Zn-BR5–2 NA-based vaccines achieved 82% spleen-specific mRNA expression and induced a strong antigen-specific CD8 + T cell response (23.09%). Notably, in a B16-OVA mouse melanoma model, Zn-BR5–2 encapsulating ovalbumin mRNA (Zn-BR5–2/mOVA) elicited potent prophylactic and therapeutic antitumor effects. This work underscores the potential of metal-LNP coordination chemistry in advancing next-generation mRNA vaccines with organ-specific delivery and heightened immunotherapeutic efficacy.
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高影响因子
Vaccines
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2026
·Vol. 14
·期 7
·581
·
IF 3.5
Ren Yang,Xiaohong Wu,Xiaowei Zhang,Shengqing Fu,Kaiping Gu,Zhe Lv,Xiaoli Li,Qunying Mao
Background:The m7G cap structure, which mimics the natural cap of eukaryotic mRNA, is a critical determinant of mRNA vaccine efficacy, safety, and stability. However, its precise quantification remains challenging due to complex impurity profiles and the high physicochemical similarity between the target cap and related impurities. Although liquid chromatography mass spectrometry (LC-MS) is widely employed for this purpose, current methodologies still face significant limitations, including labor-intensive sample preparation, low analytical throughput, poor reproducibility in quantifying low-level impurities, and a lack of universally applicable strategies across diverse mRNA vaccine platforms.Methods: We systematically optimized sample preparation and LC-MS detection workflows. RNase H-mediated cleavage was compared with DNAzymes, guide DNA probes were rationally designed, and thermostable RNase H was introduced for one-step denaturation and cleavage. To establish an accurate, efficient, and universal sample preparation workflow. Chromatographic conditions were optimized using an ion-pairing reagent system to suppress ESI-MS metal adducts. Eliminating sample purification improves recovery, reduces manual handling errors, and boosts assay efficiency.Results: Through optimally designed guide DNA probes, RNase H cleavage specificity reached ≥98% with high cleavage efficiency, offering higher efficiency than DNAzyme. Furthermore, the incorporation of thermostable RNase H enabled a single-step workflow combining high-temperature denaturation and site-specific cleavage, substantially streamlining sample preparation. On the chromatographic side, optimization of the ion-pairing reagent system effectively suppressed metal adduct formation in electrospray ionization mass spectrometry (ESI-MS). This advancement enabled direct injection of the 5′ cap fragments without purification, achieving high-recovery quantification while demonstrating broad compatibility across mainstream LC-MS platforms. The optimized assay reduces the total analytical workflow from 4~6 h to under 1.5 h.Conclusions:Combining high accuracy, robustness, and broad platform compatibility, this method offers a universal, high-throughput analytical solution for mRNA vaccine quality control and continuous process development.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-13
·
IF 10.6
Zhang Lifeng,Luo Shihua,Li Wenbin,Su Wanting,Chen Siting,Liu Chunchen,Pan Weilun,Situ Bo,Zheng Lei,Li Ling,Yan Xiaohui,Zhang Ye
Rapid and sensitive nucleic acid detection is vital in disease diagnosis and therapeutic assessment. Herein, we propose a co-freezing localized CRISPR-Cas12a (CL-Cas12a) strategy for sensitive nucleic acid detection. The CL-Cas12a was obtained through a 15-minute co-freezing process, allowing the Cas12a/crRNA complex and hairpin reporter confined on the AuNPs surface with high load efficiency, for rapid sensing of nucleic acid with superior performance to other localized Cas12a strategies. This CL-Cas12a based platform could quantitatively detect targets down to 98 aM in 30 min with excellent specificity. Furthermore, the CL-Cas12a successful applied to detect human papillomavirus infection and human lung cancer-associated single-nucleotide mutations. We also achieved powerful signal amplification for imaging Survivin mRNA in living cells. These findings highlight the potential of CL-Cas12a as an effective tool for nucleic acid diagnostics and disease monitoring.Graphical abstract
研究领域:
生物技术
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分子生物学
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诊断学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
Frontiers in Genetics
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2021
·
IF 4.599
Yang Hong,Wu Yi-Fan,Ding Jie,Liu Wei,Zhu De-Sheng,Shen Xia-Feng,Guan Yang-Tai
Background: N6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. But its role in neuromyelitis optica spectrum disorders (NMOSD) is not known.Aims: To explore the mechanism of m6A in NMOSD patients.Methods: This study assessed the m6A methylation levels in blood from two groups: NMOSD patients and healthy controls. Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) and RNA-seq were performed to assess differences in m6A methylation between NMOSD patients and healthy controls. Ultra-high performance liquid chromatography coupled with triple quadruple mass spectrometry (UPLC-QQQ-MS) method was performed to check m6A level. Differential m6A methylation genes were validated by MeRIP-qPCR.Results: Compared with that in the control group, the total m6A level was decreased in the NMOSD group. Genes with upregulated methylation were primarily enriched in processes associated with RNA splicing, mRNA processing, and innate immune response, while genes with downregulated methylation were enriched in processes associated with the regulation of transcription, DNA-templating, and the positive regulation of I-kappa B kinase/NF-kappa B signalling.Conclusion: These findings demonstrate that differential m6A methylation may act on functional genes to regulate immune homeostasis in NMOSD.
研究领域:
神经病学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）