BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Qihang Guo,Yue Mao,Jiyu Zhang,Yangyang Zhou,Yue Zhao,Ying Li,Jinglong Lv,Huiyu Yang,Bingrong Liu
Esophageal cancer, a malignant neoplasm originating from the epithelial cells of the esophagus, predominantly manifests as esophageal squamous cell carcinoma (ESCC) in approximately 90% of cases in China. Cisplatin-based chemotherapy regimens remain the first-line therapeutic option for ESCC, however, the five-year overall survival rate of patients is disappointingly low. Oridonin, a bioactive diterpenoid extracted from the traditional Chinese medicine herb Donglingcao, has demonstrated inhibitory effects against various malignancies. Currently, research on the combination of oridonin and cisplatin for the treatment of ESCC is limited. This study aims to elucidate the potential synergistic anti-cancer effects of oridonin in combination with cisplatin on ESCC, along with the underlying synergistic molecular mechanisms. In vitro experiments revealed that the combination of oridonin and cisplatin could synergistically inhibit ESCC cell proliferation, migration, invasion. The synergistic effect also induced cell cycle arrest and promoted apoptosis via the mitochondrial pathway by augmenting NOXA transcriptional activity and activating the NOXA-BCL2 axis. In vivo experiments corroborated these findings, showing a marked reduction in the growth of subcutaneous xenograft tumors in mice treated with the combination, without exacerbating the cisplatin-associated side effects such as weight loss or hepatic and renal toxicity. In conclusion, the combination of oridonin and cisplatin can synergistically inhibit the development of ESCC through the activation of the NOXA-BCL2 axis signaling pathway. This treatment is both safe and effective, presenting a promising prospect for combined therapeutic application in ESCC management.
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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中医药学
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DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2023
·Vol. 28
·期 5
·93
·
IF 3.1
Chenglong Sun,Wenhao Zheng,Linjie Wang,Quan Du
Background: Gastrodin (Gas) exhibits anti-inflammatory properties against diseases associated with the central nervous system (CNS). This study aimed to investigate the potential neuroprotective role of Gas in traumatic brain injury (TBI). Methods: A rat TBI model was established in male adult Sprague-Dawley (SD) rats by controlled cortical impingement (CCI), and lipopolysaccharide (LPS) was applied to induce the activation of BV2 microglia and HT22 hippocampal neurons. Neurological deficits, motor function and brain water content were evaluated in TBI rats. TUNEL and Nissl’s staining were applied to measure neuronal degeneration and apoptosis. Microglial activation, the mRNA and protein profiles of pro-inflammatory cytokines were tested by immunohistochemistry (IHC), quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results: Gas significantly reduced neurological deficits, cerebral edema, and neuronal apoptosis and improved motor function in TBI mice. In addition, Gas inactivated microglia and blocked the production of pro-inflammatory cytokines on the damaged side of the TBI rat brain. In vitro, Gas attenuated BV2 microglia inflammation and reduced HT22 hippocampal neuronal apoptosis. On the other hand, Gas activated the PKA/CREB/BDNF pathway both in vivo and in vitro. Conclusions: Gas blocks microglial activation-mediated inflammation through the PKA/CREB/BDNF pathway, thereby improving neurobehavioral function after TBI, which provides a potential therapeutic benefit for treating TBI.
研究领域:
神经科学
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药理学
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神经病学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-14
·
IF 9.6
Liu Min,Li Yuanyuan,Deng Zhilin,Zhang Ke,Huang Shuying,Xia Jiamin,Feng Yi,Liang Yundan,Sun Chengfu,Liu Xindong,Li Shurong,Su Bingyin,dong Yong,Huang Sizhou
Mutation in genes involved in DNA replication continuously disrupt DNA replication and give rise to genomic instability, a critical driver of oncogenesis. To prevent leukemia, immature T lymphocytes with genomic instability often undergo rapid cell death during development. However, the mechanism by which immature T lymphocytes undergo rapid cell death upon genomic instability has been enigmatic. Here we show that zebrafish mcm5 mutation leads to DNA damage in immature T lymphocytes and the immature T cells sensitively undergo rapid cell death. Detailed analyses demonstrated that the immature T lymphocytes undergo rapid apoptosis via upregulation of tp53 and downregulation of bcl2 transcription in mcm5 mutants. Mechanistically, Mcm5 directly binds to Stat1a and facilitates its phosphorylation to enhance bcl2a expression under the conditions of DNA replication stress. However, in mcm5 mutants, the absence of the Mcm5-Stat1 complex decreases Stat1 phosphorylation and subsequent bcl2a transcription, accelerating apoptosis of immature T lymphocytes with genomic instability. Furthermore, our study shows that the role of Mcm5 in T-cell development is conserved in mice. In conclusion, our work identifies a role of Mcm5 in regulating T cell development via Stat1-Bcl2 cascade besides its role in DNA replication, providing a kind of mechanism by which immature T cells with gene mutation-induced DNA damage are rapidly cleared during T lymphocyte development.
研究领域:
免疫学
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遗传学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2018
·
IF 7.877
Huipeng Li,Xue Yang,Fang Gao,Chenggen Qian,Chenzi Li,David Oupicky,Minjie Sun
In present study, gene concentrated as well as bioreduction-ruptured nanogel with local enrichment positive charge while low cytotoxicity was developed for Bcl2 siRNA delivery featured in intracellular switch on/off controlled release. Dynamic covalent bond crosslinked nanogel was formed by thiolated PEI of 1.8 kDa(PEI-1.8 kDa)and biodegradable dextrin . Once nanogel was uptake by tumor cells, high concentration of glutathione (GSH) in cytosol could bioreducible -degrade and rupture the crosslink of this dextrin nanogel (DSP) into hypotoxic PEI-1.8 kDa and dextrin, following by burst release of packed siRNA and minimizing the restriction of polymer material for siRNA transcription. This switch on/off siRNA release strategy for gene therapy exhibited equal level of the deregulation of Bcl2 protein expression determined by western blot analysis compared with cationic PEI with 25 kDa molecular weight (PEI-25 kDa) in vitro . Moreover, the gene concentrated DSP based on hypotoxic PEI-1.8 kDa and biodegradable dextrin could be administrated intravenously for systematic therapy on safely. Tumor suppression study of DSP also exhibited a superior antitumor activity in 4T1-luc tumor cell bearing BALB/C mice. Furthermore, it exhibited lower cytotoxicity, almost none hemotoxicity , moreover avoiding recognition and clearance by RES system in healthy mice. Overall, these findings suggest that this reduction-sensitive while bioreduction-ruptured polymer nanogel is an innovative strategy and holds great promise for gene and drug delivery.
研究领域:
癌症治疗
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基因递送
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纳米技术
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药学科学
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产品关联
DOI
PubMed
高影响因子
Cancer Medicine
·
2021
·Vol. 10
·期 10
·3358-3372
·
IF 4.452
Dingsheng Liu,Chunsheng Chen,Mingming Cui,Hong Zhang
Recent studies have identified microRNAs (miRNAs) as a compelling novel class of biomarker in colorectal cancer (CRC) development and metastasis. Here, we demonstrated that the level of plasma exosomal miR-140-3p in CRC patients was lower than that in healthy controls. The decreased miR-140-3p level was also observed in CRC patients with liver metastasis. The expression of miR-140-3p in CRC tissues were significantly lower than that in matched normal tissues. Functionally, miR-140-3p overexpression suppressed proliferation, migration, invasion, and β-catenin nuclear translocation, as well as promoted apoptosis in LoVo cells, while inhibition of miR-140-3p reversed these cellular processes in HCT 116 cells. Notably, BCL9 and BCL2 were recognized as direct targets of miR-140-3p. BCL9 knockdown abrogated miR-140-3p inhibitor-induced effects on HCT 116 cells with decreased proliferation, migration, and invasion. BCL2 knockdown increased apoptosis of miR-140-3p inhibitor-transfected HCT 116 cells. In vivo experiments revealed that miR-140-3p overexpression inhibited tumor growth in LoVo xenograft model and diminished metastatic nodules in nude mice liver. Taken together, this work supports that miR-140-3p exerts as a tumor suppressor in CRC progression via targeting BCL9 and BCL2, and suggests miR-140-3p-BCL9/BCL2 axis may be applied in miRNA-based therapy and prognostication of CRC.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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遗传学
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DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Liu Senyue,Luo Lin,Zuo Fengyuan,Geng Yi,Ou Yangping,Chen Defang,Yang Shiyong,Luo Wei,Wang Yan,Wang Jun,Huang Xiaoli
Myxobolus, a major harmful type of myxospora, is one of the main parasitic pathogens of freshwater fish. Once myxoboliosis occurs, treatment can be extremely difficult. Therefore, clear understandings of the etiology of myxoboliosis and its pathological mechanism are keys for prevention and control. Here, histology, transmission electron microscopy, transcriptome study, tunel assay, and immunohistochemistry were carried out, revealing the morphology, pathological effects as well as host response mechanism of goldfish gill to Myxobolus ampullicapsulatus. Histological studies showed that the mature spores of Myxobolus ampullicapsulatus were composed of three parts, the spore shell, sporoplasm and bottle shaped polar capsule containing double S-shaped polar filaments. Transcriptome analysis revealed that Myxobolus ampullicapsulatus -infected (Myx) goldfish gills were characterized by apoptosis activation mediated by “p53 signaling pathway” with significantly up-regulated apoptosis-related differential genes dominated by p53-Bcl2/Bax signaling pathway. In addition, tunel assay revealed severe gill apoptosis in the Myx group. Transcriptome analysis also revealed that Myx group showed changes in immune response and significantly down-regulated immune-related differential genes. Beyond that, immunohistochemistry showed that there was no significant increase in the number of gill lymphocyte after parasite infection. These results suggest that the pathological mechanism of Myxobolus ampullicapsulatus infection on gills of goldfish may be related to apoptosis and immunosuppression. Subsequent qRT-PCR showed that apoptosis-related genes (Caspase3,Bad, Bax) and anti-inflammatory gene IL-10 were significantly increased, while immune-related pro-inflammatory genes (IL-1β, IL-8) were markedly down-regulated, further verifying the transcriptome results. Based on the above results, we concluded that p53-Bcl2/Bax related networks that dominant the expression of apoptosis genes were activated while immunity was suppressed in the gills of Myxobolus ampullicapsulatus infected goldfish. Our study is not only of benefit to enrich the taxonomy of Myxobolus but also clarifies its pathogenic mechanism, thus providing targets for prevention and control of myxoboliosis.
研究领域:
鱼类病理学
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分子生物学
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寄生虫学
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免疫学
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转录组学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2022
·
IF 10.633
Bin Liang,Dawei Jiang,Luqi Pan,Fang Xiong,Shuya Feng,Shenghao Wu,Haige Ye,Zhijie Yu,Changcan Shi,Shenmeng Gao
Selective BCL2 inhibitor ABT-199 has been approved to treat hematological malignancies including acute myeloid leukemia (AML). However, acquired drug resistance and severe side effects occur after extended treatment limiting the clinical usage of ABT-199. Here, we successfully encapsulated pure ABT-199 in amphiphilic mPEG- b -PTMC 169 block copolymer , forming mPEG-b-PTMC 169 @ABT-199 nanoparticles (abbreviated as PEG-ABT-199), which presented better aqueous dispersion and higher efficiency of loading and encapsulation than pure ABT-199. We then compared the anti-leukemic ability of pure ABT-199 and PEG-ABT-199 in vitro and in vivo . PEG-ABT-199 had a lower IC50 value compared with pure ABT-199 in MV4-11 and MOLM-13 cell lines. In addition, PEG-ABT-199 significantly induced apoptosis and decreased colony number than pure ABT-199. Most importantly, PEG-ABT-199 markedly reduced leukemic burden, inhibited the infiltration of leukemic blasts in the spleen, and extended the overall survival (OS) in MLL-AF9-transduced murine AML compared with free ABT-199. Meanwhile, the blank PEG169 NP was non-toxic to normal hematopoiesis in vitro and in vivo , suggesting that PEG169 NP is a safe carrier. Mechanistically, PEG-ABT-199 enhanced mitochondria-targeted delivery of ABT-199 to trigger the collapse of mitochondrial membrane potential (MMP), the release of cytochrome c (cyt-c), and mitochondria-based apoptosis. In conclusion, our results suggest that PEG-ABT-199 has more vital anti-leukemic ability than pure ABT-199. PEG-ABT-199 has potential application in clinical trials to alleviate side effects and improve anti-leukemia ability. Statement of significance ATB-199, an orally selective inhibitor for BCL2 protein, presents marked activity in relapsed or refractory AML, T-ALL, and CLL patients. However, ABT-199 resistance severely limits the further clinical usage because of off-target effects, non-specific toxicities, and low delivery of drugs. To reduce the side-effects and improve the solubility and bioavailability, ABT-199 was encapsulated into the amphiphilic mPEG- b -PTMC block copolymer by co-assembly method to obtain mPEG- b [email protected] nanoparticles (PEG-ABT-199). PEG-ABT-199 has several advantages compared with pure ABT-199. 1.PEG-ABT-199 presents better aqueous dispersion and higher efficiencies of loading and encapsulation than pure ABT-199. 2. PEG-ABT-199 substantially enhances the anti-leukemic ability in vitro and in vivo compared with pure ABT-199. 3. PEG-ABT-199 has little effects on normal cells. 4. PEG-ABT-199 can reduce treatment cost.
研究领域:
药理学
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肿瘤学
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纳米技术
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血液学
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产品关联
DOI
PubMed
高影响因子
Reproductive Biology and Endocrinology
·
2021
·Vol. 19
·期 1
·1-11
·
IF 5.211
Xu Haopeng,Xia Yi,Qin Juan,Xu Jie,Li Chongyan,Wang Yan
Background Premature ovarian failure (POF) is a common disease in the field of Gynecology. Low intensity pulsed ultrasound (LIPUS) can promote tissue repair and improve function. This study was performed to determine the effects of LIPUS on granulosa cells (GCs) apoptosis and protein expression of B-cell lymphoma-2 (Bcl-2) and BCL2-Associated X (Bax) in 4-vinylcyclohexene diepoxide (VCD)-induced POF mice and investigate the mechanisms of LIPUS on ovarian function and reserve capacity.Methods The current POF mice model was administrated with VCD (160 mg/kg) by intraperitoneal injection for 15 consecutive days. The mice were divided into the POF group, LIPUS group and control group. In the LIPUS group, the right ovary of mice was treated by LIPUS (acoustic intensity was 200 mW/cm2, frequency was 0.3 MHz, and duty cycle was 20%) for 20 min, 15 consecutive days from day 16. The mice of the POF group and control group were treated without ultrasonic output. The basic observation and body weight were recorded. Hematoxylin and eosin staining (H&E staining) and enzyme-linked immunosorbent assay (ELISA) were applied to detect ovarian follicle development, ovarian morphology and sex hormone secretion. Ovarian GCs apoptosis was detected by TUNEL assay and immunohistochemistry.Results The results showed that VCD can induce estrus cycle disorder, follicular atresia, sex hormone secretion decreased and GCs apoptosis in mice to establish POF model successfully. LIPUS significantly promoted follicular development, increased sex hormone secretion, inhibited excessive follicular atresia and GCs apoptosis. The mechanism might be achieved by increasing the protein expression of Bcl-2 and decreasing the expression of Bax in ovaries.Conclusion sLIPUS can improve the POF induced by VCD. These findings have the potential to provide novel methodological foundation for the future research, which help treat POF patients in the clinic.
研究领域:
妇科学
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生殖医学
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分子生物学
·
超声治疗
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DOI
PubMed
高影响因子
Antioxidants
·
2026
·Vol. 15
·期 3
·279
·
IF 8.2
Yadong Zhang,Zhenao Zhang,Huanting Pei,Chongyue Zhang,Xiaolong Zhang,Simeng Qiao,Siqi Zhu,Ziyi Wang,Jingyi Ren,Yuxia Ma
Studies show microplastics (MPs) impair lung function directly and indirectly, yet effective solutions are lacking. In light of this, sesamin (Ses), a natural lignan-like compound with diverse pharmacological properties, may offer protection. The study aims to investigate whether Ses pretreatment can mitigate MPs-induced lung damage and to elucidate the underlying mechanisms. Male C57BL/6 mice received MPs (10,000 μg/L) in drinking water, with varying Ses doses gavaged daily for 28 days. Computational pharmacology and in vivo/in vitro experiments, including histology, immunofluorescence, and western blot, were used to elucidate Ses’s protective mechanisms. In vivo experiments showed Ses can alleviate MPs-induced histopathological alterations, inflammatory responses, and oxidative stress in lung tissue. Computational pharmacology suggested that the protective mechanism of Ses may be associated with the apoptotic signaling pathway, with Bcl2 as its potential target. Both in vivo and in vitro studies demonstrated that Ses significantly upregulates Bcl2 expression while downregulating Bax and Casp3. Notably, a Bcl2 inhibitor substantially attenuated Ses’s protective effects. Our research suggests that Ses can mitigate MPs-induced lung injury by modulating the apoptotic signaling pathway, with Bcl2 identified as a key target. Dietary supplementation may represent a promising intervention strategy for preventing and managing food safety risks associated with MPs.
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产品关联
DOI
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2018
·
IF 5.091
Weixia Xu,Pengjin Ge,Boning Niu,Xiaokun Zhang,Jie Liu,Jingjing Xie
The abundance of B cell lymphoma gene 2 (Bcl-2) is closely correlated with the resistance of cancer cells to chemotherapeutic agents, and a peptide derived from orphan nuclear receptor Nur77 can convert Bcl-2 from a protector to a killer of cancer cells. However, successful application of the Bcl-2-converting peptide to treat drug-resistant cancer cells depends on an efficient delivery carrier. Mesoporous silica nanoparticles (MSNs) have been extensively studied as promising candidates for small molecule drug delivery. However, the effective encapsulation and intracellular delivery of peptides using small pore-sized MSNs still remain a great technical challenge. In this paper, an effective delivery platform for Bcl-2-converting peptide was fabricated by us to treat multidrug resistant-cancer cells via tuning the surface functionality of macroporous silica nanoparticles. The resulting large-sized pore silica nanoparticles, especially those modified with thiol group, exhibited the high Bcl-2-converting peptide-loading efficiency of over 40%. Moreover, the peptide induced MCF7/DOX cells into apoptotic status by penetrating cytomembrane into mitochondria and being bound with Bcl-2 to expose the BH3 domain with the aid of various surface functionalities-decorated MSNs. In particular, amine-modified surface of MSNs caused the greater influence on the cell apoptosis-inducing effects of peptide in comparison with other functionalities-modified ones. Taken together, our study, for the first time, demonstrates a special approach towards pore size and surface functionality-collectively modulated silica-based nanostructural material for effective delivery of bio-macromolecules (e.g., Bcl-2-converting peptide) to treat the multidrug resistant-cancer cells with elevated Bcl-2 levels.
研究领域:
纳米技术
·
癌症生物学
·
药学
·
材料科学
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DOI
PubMed
高影响因子
Results in Chemistry
·
2025
·
IF 4.2
Jiabao Cai,Qian Zhang,Jiani Fan,Shengguang Chen
Baicalin, a flavonoid derived from Scutellaria baicalensis, exhibits broad antitumor activity. However, its effects on anaplastic thyroid cancer (ATC) C643 cells remain unclear. This study investigated the inhibitory capacity and underlying mechanisms of baicalin against C643 cells using both in vitro and in vivo models. In vitro, including CCK-8 viability assay, scratch-wound healing assay, Transwell migration, Annexin V-FITC/PI apoptosis, cell-cycle and JC-1 mitochondrial membrane potential assays demonstrated that baicalin reduced cell viability and migration in a concentration-and time-dependent manner, induced G2-phase arrest and decreased mitochondrial membrane potential. Integrated transcriptome sequencing identified BCL2 and the PI3K-AKT pathway as key targets. qPCR and Western blot confirmed that baicalin down-regulated BCL2 in a dose-dependent manner, selectively activated the PI3K-AKT cascade, promoted TP53 recruitment to the BAX/BIM promoters and up-regulated their transcription, accompanied by increased p-PI3K and p-AKT levels. In vivo, daily intraperitoneal administration of 50 mg/kg baicalin for 21 days led to a 55.6 % reduction in C643 xenograft volume. Immunohistochemistry revealed decreased BCL2 and Ki-67 expression in tumor tissues, indicating impaired anti-apoptotic activity and proliferative capacity. Importantly, histopathological examination of major organs (heart, liver, spleen, lung and kidney) showed no treatment-related toxicity, confirming the safety of baicalin. These findings demonstrate that baicalin is a safe, multi-target therapeutic candidate with a well-defined mechanism, offering a novel and effective targeted option for aggressive anaplastic thyroid cancer.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
天然产物研究
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细胞生物学
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产品关联
DOI
高影响因子
NANOTECHNOLOGY
·
2021
·Vol. 33
·期 8
·085103
·
IF 3.874
Xiuli Zhang,Ruqing Gao,Huiyu Yan,Zijian Zhao,Jun Zhang,Weiming You
Bcl-2, an anti-apoptotic protein, is always overexpressed in tumor cells to suppress the pro-apoptotic function of Bax, thereby prolonging the life of the tumor. However, BH3 proteins could directly activate Bax via antagonizing Bcl-2 to induce apoptosis in response to the stimulation. Thus, mimicking BH3 proteins with a peptide is a potential strategy for anti-cancer therapy. Unfortunately, clinical translation of BH3-mimic peptide is hindered by its inefficacious cellular internalization and proteolysis resistance. Herein, we translated a BH3-mimic peptide into a peptide-auric spheroidal nanocluster (BH3-AuNp), in which polymeric BH3-Auric precursors [Au1+-S-BH3]n are in situ self-assembled on the surface of gold nanoparticles by a one-pot synthesis. Expectedly, this strategy could improve the anti-proteolytic ability and cytomembrane penetrability of the BH3 peptide. As a result, BH3-AuNp successfully induced the apoptosis of two cancer cell lines by an order of magnitude compared to BH3. This therapeutic and feasible peptide nano-engineering strategy will help peptides overcome the pharmaceutical obstacles, awaken its biological functions, and possibly revive the research about peptide-derived nanomedicine.
研究领域:
生物化学
·
纳米医学
·
肿瘤学
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DOI
PubMed
高影响因子
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