MICROCHIMICA ACTA
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2026
·Vol. 193
·期 1
·58
·
IF 5.3
Yin Zhaojiang,Zhang Jing,Li Binghui,Fan Hao,Wang Mei,Cui Hanfeng
A dual-mode sensor based on intramolecular catalytic hairpin assembly strategy (intra-CHA) is proposed for Survivin mRNA detection. Intra-CHA, a triplex complex of tetraferrocene-labeled H1/H2, shortens H1-H2 distance and increases their local concentrations, accelerating reaction by 2.8-fold vs. free-CHA. Ruthenium-based covalent organic frameworks (RuCOFs) with Ru(dcbpy) 3 2+ as luminophore has dual fluorescence-electrochemiluminescence (FL-ECL) properties. EDTA-incorporated RuCOFs@EDTA expands active sites, enhancing ECL efficiency 8-fold. Intra-CHA system is covalently conjugated to RuCOFs@EDTA through amide bond linkages. Target mRNA-triggered strand displacement reactions induce structural reconfiguration of the intra-CHA probes, resulting in controlled spatial segregation of tetraferrocene from the RuCOFs@EDTA interface. This results in the recovery of FL and ECL signals, enabling rapid and highly sensitive detection of Survivin mRNA. Experimental results show that the detection limits reach 0.04 fM (in the FL mode) and 0.009 fM (in the ECL mode) respectively, with excellent selectivity, stability, and reproducibility. The system has been successfully applied to detect Survivin mRNA in actual serum samples, providing a novel strategy for Survivin mRNA detection and paving the way for developing future diagnostic strategies for early cancer screening. Graphical
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PLoS Pathogens
·
2026
·Vol. 22
·期 5
·e1014007
·
IF 4.9
Xuejun Zhao,Xinyi Wang,Kejun Liu,Qian Fang,Cheng Wang,Guangbo Mei,Lihua Qu,Jiaxi Zhang,Jiayi Feng,Wenjuan Yang,Junnan Zhu,Hang Zhuo,Na Kuang,Xuebing Qiu,Zhigao Deng,Qiong Luo,Xiaoxia Jin,Lanxuan Jiang,Xiaoqing Li,Huifen Dong,Rui Zhou
Inhibiting the activation of hepatic stellate cells (HSCs) represents a key therapeutic strategy for alleviating liver fibrosis induced by schistosomiasis. Diverse cell populations secrete pro-inflammatory cytokines and chemokines, which induce HSC activation and thereby promote hepatic fibrosis progression. Tristetraprolin (TTP) exerts a pivotal role in the post-transcriptional regulation of pro-inflammatory cytokines by either accelerating mRNA degradation or suppressing translation, a regulatory mechanism closely associated with the pathogenesis of various hepatic disorders. However, the pathological roles of TTP in Schistosoma japonicum -induced liver fibrosis remain largely elusive. Here, we report that TTP is upregulated in the liver during S. japonicum -induced liver fibrosis, and its overexpression markedly ameliorates this fibrotic pathology in vivo . We further identify that TTP negatively regulates TGF-β1 mRNA stability by promoting N6-methyladenosine (m 6 A) RNA methylation, thereby inhibiting HSC activation. Mechanistically, TTP enhances transcription of the WT1-associated protein ( WTAP ) gene through its interaction with SMAD2/3. Furthermore, treatment with an m 6 A RNA methylation inhibitor confirms that TTP-mediated protection against S. japonicum -induced liver fibrosis, an effect associated with increased m⁶A RNA methylation in vivo . Thus, our findings uncover a novel and critical role of TTP in exerting its anti-fibrotic function via the WTAP/m 6 A epitranscriptomic machinery in the pathogenesis of S. japonicum -induced liver fibrosis. This finding provides a rationale for the therapeutic targeting of TTP-mediated m 6 A RNA methylation in S. japonicum -induced liver fibrosis.
Activation of hepatic stellate cells (HSCs) represents a pivotal event in the progression of schistosomiasis-induced liver fibrosis. Pro-inflammatory cytokines and chemokines secreted by injured hepatocytes and activated macrophage induce HSC activation. However, the underlying mechanisms governing the fine-tuned regulation of pro-inflammatory cytokines and chemokines gene expression during the progression of schistosomiasis-induced liver fibrosis remain largely elusive. As a key negative regulator of immune responses, the role of TTP in liver fibrosis remains controversial. Furthermore, while TTP has been reported to act as a transcriptional co-regulator and modulate gene expression at the transcriptional level, the majority of TTP-related studies have centered on its canonical role as a key mediator of mRNA degradation. Here, our study demonstrates that TTP attenuates S. japonicum -induced liver fibrosis via the regulation of TGF-β1 mRNA stability in an m 6 A-dependent manner. Specifically, WTAP-mediated m⁶A RNA methylation of TGF-β1 mRNA exerts a suppressive effect on HSC activation, thereby mitigating S. japonicum -induced liver fibrosis. Notably, our findings uncover a previously uncharacterized regulatory mechanism whereby TTP promotes WTAP transcription via direct interaction with SMAD2/3. These results demonstrate that TTP-driven transcriptional regulation of WTAP represents a novel mechanism underlying HSC activation, and further identify a potential strategy for intervening in S. japonicum -induced liver fibrosis.
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高影响因子
BRAIN RESEARCH
·
2025
·
IF 2.6
Shan Hui,Yi Long,Lemei Zhu,Wei Shi,Qing Zheng,Lihui Liang
Background Alzheimer’s disease (AD) is characterized by cognitive decline and neuronal loss, with cellular senescence emerging as a key driver. The insulin-like growth factor-1 receptor (IGF1R) pathway is implicated in aging and AD pathology. IGF2 mRNA binding protein 2 (IGF2BP2) can stabilize IGF1R mRNA, but its role in AD-associated neuronal senescence remains unclear. Methods We established AD mouse models and H 2 O 2 -induced senescent neuronal cell models to explore the impact of IGF2BP2 in neuronal senescence and cognitive deficits. RNA pull-down assays, methylated RNA immunoprecipitation (MeRIP)-qPCR, and behavioral tests were used to elucidate the molecular mechanisms and therapeutic potential of targeting IGF2BP2. Results IGF2BP2 was significantly up-regulated in the hippocampal neurons of AD mice. This upregulation correlated with increased β-amyloid (Aβ) deposition, neuronal damage, and cognitive impairments. In vitro , IGF2BP2 knockdown in H 2 O 2 -induced senescent neurons reduced IGF1R expression and alleviated neuronal senescence, as evidenced by decreased senescence-associated secretory phenotype factors and improved cell viability. Mechanistically, IGF2BP2 stabilized IGF1R mRNA through m6A modification, enhancing its expression. Knockdown of IGF2BP2 decreased IGF1R mRNA stability and expression, thereby mitigating neuronal senescence. In AD mice, IGF2BP2 knockdown improved cognitive function, reduced Aβ deposition, and delayed neuronal senescence. Conclusion IGF2BP2 contributes to neuronal senescence and cognitive deficits in AD by regulating IGF1R expression through m6A modification.
研究领域:
神经科学
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分子生物学
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表观遗传学
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衰老研究
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神经退行性疾病
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Experimental and Therapeutic Medicine
·
2024
·Vol. 27
·期 5
·1-8
·
IF 2.4
Yunyan Tang,Hongfang Li,Jianhua Tang,Lei Hu,Feifei Ma,Yanmiao Liu,Fushan Tang
Total saikosaponins (TSS) form a group of chemically and biologically active components that can be extracted from Bupleurum, with reported antidepressive, anti‑inflammatory, antiviral, antiendotoxin, antitumor, anti‑pulmonary fibrosis and anti‑gastric ulcer effects. Bupleurum or TSS is frequently utilized in clinical practice alongside other medications (such as entecavir, lamivudine, compound paracetamol and amantadine hydrochloride capsules), leading to an increased risk of drug‑drug interactions. The cytochrome P450 (CYP) family serves a critical role in the metabolism of numerous essential drugs (such as tamoxifen, ibuprofen and phenytoin), where the majority of drug interactions involve CYP‑mediated metabolism. It is therefore essential to understand the effects of key components of Bupleurum on CYPs when administering combination therapies containing TSS or Bupleurum. The present study aimed to investigate the effects of TSS on the mRNA and protein expression of CYP3A4 and CYP1A2 in HepaRG cells. The effects of TSS on the survival of HepaRG cells was investigated using the Cell Counting Kit‑8 (CCK‑8) method. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot (WB) analysis were used to assess the effects of different concentrations of TSS (0, 5, 10 and 15 µg/ml) on CYP3A4 and CYP1A2 mRNA and protein expression in HepaRG cells. Based on the CCK‑8 assay results, it was observed that the cell viability remained above 80% when treated with 1, 5, 10 and 15 µg/ml TSS. Although there was a statistically significant reduced cell viability at TSS concentrations of 10 and 15 µg/ml compared with the control group, the findings indicated that TSS did not exhibit notable cytotoxic effects at these concentrations. Furthermore, RT‑qPCR results revealed that compared with those in the control group, TSS at concentrations of 10 and 15 µg/ml reduced CYP3A4 mRNA expression but increased CYP1A2 mRNA expression in HepaRG cells at concentrations of 15 µg/ml. WB analysis found that TSS at concentrations of 10 and 15 µg/ml downregulated CYP3A4 protein expression in HepaRG cells while increasing CYP1A2 protein expression at concentrations of 15 µg/ml. Results in the present study suggest that TSS can inhibit CYP3A4 mRNA and protein expression, but exerts opposite effects on their CYP1A2 counterparts. These findings suggest that it is necessary to consider drug interactions between clinical preparations containing TSS or Bupleurum and drugs metabolized by CYP3A4 and CYP1A2 to avoid potential adverse drug reactions in clinical practice.
研究领域:
药理学
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分子生物学
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毒理学
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药物代谢
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ACTA PHARMACOLOGICA SINICA
·
2012
·Vol. 33
·期 7
·909-917
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IF 1.953
Wang Xin-ting,Li Jia,Liu Li,Hu Nan,Jin Shi,Liu Can,Mei Dan,Liu Xiao-dong
Aim: Diabetes is associated with elevated serum total cholesterol level and disrupted lipoprotein subfractions. The aim of this study was to examine alterations in the tissue cholesterol contents closely related to diabetic complications. Methods: Intraperitoneal injection of streptozotocin was used to induce type 1 diabetes in adult male Sprague-Dawley rats. On d 35 after the injection, liver, heart, intestine, kidney, pancreas, cerebral cortex and hippocampus were isolated from the rats. The content of total and free cholesterol in the tissues was determined using HPLC. The ATP-binding cassette protein A1 (ABCA1) protein and ApoE mRNA were measured using Western blot and QT-PCR analyses, respectively. Results: In diabetic rats, the level of free cholesterol was significantly decreased in the peripheral tissues, but significantly elevated in hippocampus, as compared with those in the control rats. Diabetic rats showed a trend of decreasing the total cholesterol level in the peripheral tissues, but significant change was only found in kidney and liver. In diabetic rats, the level of the ABCA1 protein was significantly increased in the peripheral tissues and cerebral cortex; the expression of ApoE mRNA was slightly decreased in hippocampus and cerebral cortex, but the change had no statistical significance. Conclusion: Type 1 diabetes decreases the free cholesterol content in the peripheral tissues and increases the free cholesterol content in hippocampus. The decreased free cholesterol level in the peripheral tissues may be partly due to the increased expression of the ABCA1 protein.
研究领域:
内分泌学
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代谢学
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药理学
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神经科学
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ACTA PHARMACOLOGICA SINICA
·
2020
·Vol. 42
·期 7
·1190-1194
·
IF 5.064
Shen Zhu-qing,Wang Juan,Tan Wen-fu,Huang Tao-min
Hedgehog plays an important role in a wide range of physiological and pathological conditions. Paracrine activation of Hedgehog pathway in stromal cells increases the expression of VEGF, which promotes neovascularization in colorectal cancer and ultimately the growth of colorectal cancer. Berberine (BBR) has anticancer activity. In this study we investigated whether BBR inhibited the growth of colon cancer through suppressing the paracrine sonic hedgehog (SHH) signaling in vitro and in vivo. We showed that BBR (1–10 μM) dose-dependently inhibited the secretion and expression of SHH protein in HT-29 and SW480 cells. BBR did not influence the transcription of SHH, but promoted the degradation of SHH mRNA, thus decreased the SHH mRNA expression in the colorectal cancer cells. In nude mice bearing HT-29 xenograft, oral administration of BBR (100 mg · kg − 1 · d −1 ) or a positive control drug GDC-0449 (100 mg · kg −1 · d −1 ) for 4 weeks markedly suppressed the growth of HT-29 tumor with BBR exhibiting a better antitumor efficacy. The tumor growth inhibition caused by BBR or GDC-0449 was comparable to their respective inhibitory effect on the mouse-specific Gli mRNA expression in the tumor. However, BBR (20 μM) did not affect the expression of human transcription factor Gli1 mRNA in HT-29 and SW480 cells. In conclusion, BBR promotes the degradation of SHH mRNA in colorectal cancer cells, interrupting the paracrine Hedgehog signaling pathway activity thus suppresses the colorectal cancer growth. This study reveals a novel molecular mechanism underlying the anticancer action of BBR.
研究领域:
肿瘤学
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分子生物学
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药理学
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Drug Design Development and Therapy
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2020
·
IF 3.216
Hongfang Li,Yunyan Tang,Yang Wang,Weipeng Wei,Chengchen Yin,Fushang Tang
Background Bupleurum is one of the most important traditional Chinese medicines and an ingredient in many compound preparations. It is widely used together with other drugs in clinical practice, and thus there is great potential for drug–drug interactions. Saikosaponin D (SsD) is a major bioactive triterpenoid saponin extracted from Bupleurum with anti-inflammatory, anticancer, antioxidative, and antihepatic fibrosis effects. Effects of the main components of Bupleurum on cytochromes P450 (CYPs) need to be clarified in the clinical application of combination therapies of formulations containing SsD or Bupleurum . Purpose This study aimed to investigate the effects of SsD on the CYP1A2 and CYP2D6 mRNAs, protein expression, and relative enzyme activities in HepaRG cells. Methods HepaRG cells were cultured with SsD at concentrations of 0.5, 1, 5 and 10 μM for 72 hours. mRNA and protein expression of CYP1A2 and CYP2D6 were analyzed with real-time PCR and Western blot analysis. Relative enzyme activities were analyzed with HPLC based on consumption of the specific probe substrate. Results SsD significantly induced expression of mRNA and increased relative activity of CYP1A2 in HepaRG cells after the cells had been treated with SsD at concentrations of 1, 5 and 10 μM. SsD also induced protein expression of CYP1A2 at concentrations of 5 and 10 μM. SsD exhibited an inductive effect on CYP2D6 mRNA and protein expression, while increasing the relative activity of CYP2D6 at concentrations of 5 and 10 μM. Conclusion This study is the first to investigate the effect of SsD on CYP1A2 and CYP2D6 in HepaRG cells, and the results may provide some useful information on potential drug–drug interactions related to clinical preparations containing SsD or Bupleurum .
研究领域:
药理学
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毒理学
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分子生物学
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中药学
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ANALYTICAL CHEMISTRY
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2021
·
IF 6.986
Xiaoqing Wu,Cheng Che,Xinmeng Wang,Qiujiao Du,Huageng Liang,Pengcheng Gao,Fan Xia
DNA species are recognized as a powerful probe for nanochannel analyses to address the issues of specific target recognition and highly efficient signal conversion due to their programmable and predictable Watson–Crick bases. However, in the conventional view, abundant sophisticated DNA structures synthesized by DNA amplification strategies are unsuitable for use in nanochannel analyses owing to their low probability to enter a nanochannel restricted by the smaller opening of the nanochannel, as well as the faint ion signal produced by the steric effect. Here, we present an integrated strategy of nanochannel analyses that combines the target recognitions by encoded rolling circle amplification (RCA) in solution and the ionic signal enhancement by the space charge effect through the immobilization of highly negative-charged RCA amplicons on the outer surface of the nanochannels. Owing to the highly negative-charged RCA amplicons with 100 nm sizes, a sharp increase of ionic current up to 7454% has been achieved. The RCA amplicon triggered by mRNA-21 on the outer surface of the poly(ethylene terephthalate) membrane with a single nanochannel realized the single-base mismatch detection of mRNA-21 with a sensitivity of 6 fM. The DNA amplicon endows the nanochannel with high sensitivity and selectivity that could extend to other applications, such as DNA sequencing, desalination, sieving, and water–energy nexus.
研究领域:
生物物理学
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纳米技术
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分子生物学
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分析化学
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Cellular & Molecular Immunology
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2022
·Vol. 19
·期 5
·602-618
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IF 22.096
Ma Xiaojian,Tan Xi,Yu Bingbing,Sun Wanwei,Wang Heping,Hu Huijun,Du Yanyun,He Ruirui,Gao Ru,Peng Qianwen,Cui Zhihui,Pan Ting,Feng Xiong,Wang Junhan,Xu Chengqi,Zhu Bin,Liu Wei,Wang Chenhui
Fungal infections cause ~1.5 million deaths each year worldwide, and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria. The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species. Therefore, a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies. Here, we report that DOCK2 (dedicator of cytokinesis 2) promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages. DOCK2-deficient macrophages exhibit decreased RAC GTPase (Rac family small GTPase) activation and ROS (reactive oxygen species) production, which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways. Mechanistically, after fungal stimulation, activated SYK (spleen-associated tyrosine kinase) phosphorylates DOCK2 at tyrosine 985 and 1405, which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation. Importantly, nanoparticle-mediated delivery of in vitro transcribed (IVT) Rac1 mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo. Taken together, this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.
研究领域:
免疫学
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微生物学
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分子生物学
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药理学
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ELECTROANALYSIS
·
2022
·Vol. 35
·期 4
·e202200330
·
IF 3.077
Ting Huang,Wenxing Zhang,Guobing Wie,Nian Hong,Mei Wang,Qiqi Fan,Qiangqiang Yu,Fusheng Liao,Hao Fan
Herein, a reagentless electrochemical DNA sensor based on a self-powered DNA machine for detecting survivin mRNA in cells is developed. The metal-organic framework (MOFs) loaded with DNAzyme cofactors (Mn 2+ ) is coated on PTFE rods on the Au surface and assembled with the DNA walker, overcoming the complexity of adding metal ions from the external environment. In addition, the orbital chain is modified by a synthetic bisferrocene signal marker, which further enables signal amplification. Under optimal conditions, the sensor exhibits a range from 1×10 −14 mol/L to 1×10 −8 mol/L with a detection limit (S/N=3) of 1.28 fM.
研究领域:
生物传感技术
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分子生物学
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纳米材料科学
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高影响因子
PLANT CELL
·
2024
·
IF 10
Wu Xinyang,Chen Shuting,Zhang Zixin,Zhou Weixin,Sun Ting,Ning Kang,Xu Min,Ke Xubo,Xu Pei
Virus-induced drought tolerance presents a fascinating facet of biotic-abiotic interaction in plants, yet its molecular intricacies remain unclear. Our study shows that cowpea mild mottle virus (CPMMV) infection enhances drought tolerance in common bean (Phaseolus vulgaris) plants through a virus-derived small interfering RNA (vsiRNA)-activated autophagy pathway. Specifically, a 21-bp vsiRNA originating from the CPMMV Triple Gene Block1 (TGB1) gene targeted the 5' untranslated region (UTR) of the host Teosinte branched 1, Cycloidea, Proliferating Cell Factor (TCP) transcription factor gene PvTCP2, independent of the known role of TGB1 as an RNA silencing suppressor. This targeting attenuated the expression of PvTCP2, which encodes a transcriptional repressor, and in turn upregulated the core autophagy-related gene (ATG) PvATG8c, leading to activated autophagy activity surpassing the level induced by drought or CPMMV infection alone. The downstream EARLY RESPONSIVE TO DEHYDRATION (ERD) effector PvERD15 is a homologue of Arabidopsis thaliana AtERD15, which positively regulates stomatal aperture. PvERD15 was degraded in PvATG8c-mediated autophagy. Therefore, we establish a TGB1-PvTCP2-PvATG8c-PvERD15 module as a trans-kingdom fine-tuning mechanism that contributes to virus-induced drought tolerance in plant-drought-virus interactions.
研究领域:
植物病毒学
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分子生物学
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植物生理学
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Journal of Materials Chemistry B
·
2023
·
IF 7
Yanhao Zhang,Ji Wang,Hanlei Xing,Chao Liu,Wenhui Zha,Shuo Dong,Yuhao Jiang,Xinsong Li
mRNA vaccines have emerged as a highly promising approach for preventing cancer and infectious diseases, attributed to their superior immunogenicity, rapid development speed, and quality-controlled scale production. While homologous mRNA vaccine administration is currently the most prevalent method employed in clinical settings, heterologous administration is a promising avenue worth exploring. In this report, two types of mRNA vaccine formulations for SARS-CoV-2 infection were developed based on different lipid nanoparticle (LNP) delivery systems, and heterologous and homologous mRNA vaccinations were administered to explore the levels of immune responses comparatively. First, five novel H-series ionizable lipids were synthesized and confirmed by NMR and MS. Subsequently, six SARS-CoV-2 receptor-binding domain (RBD) mRNA-encapsulated LNP formulations were prepared using a microfluidic mixer based on H-series and MC3 lipids. These formulations exhibited spherical structures with an average diameter ranging from 90–140 nm, as characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The safety of these formulations was confirmed in vitro by the cytotoxicity assay. Moreover, transfection assay, lysosomal escape test, and western blot, and in vivo biodistribution analyses collectively demonstrated that lipids H03 and MC3 exhibited superior in vitro and in vivo delivery efficacy in comparison to other H-series lipids. Notably, H03-Fluc mRNA exhibited an approximately 2.2-fold higher in vivo bioluminescence signal intensity than MC3-Fluc mRNA. Additionally, evaluation of humoral immunity demonstrated that homologous H03-mRNA vaccination elicited an immune response that was approximately 3-fold higher than that of homologous MC3-mRNA vaccination. More significantly, the heterologous H03-mRNA/MC3-mRNA vaccination elicited an immune response that was approximately 2-3-fold higher than that of homologous H03-mRNA vaccination and 6–9-fold higher than that of homologous MC3-mRNA vaccination, without any observable adverse effects. These results suggest that heterologous mRNA vaccination is superior to homologous mRNA vaccination and may be attributed to differences in LNP carriers. Therefore, our research may inspire further exploration of different delivery systems to enhance mRNA-based therapeutics.
研究领域:
病毒学
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免疫学
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药学
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生物技术
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高影响因子
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