Journal of Materials Chemistry B
·
2018
·Vol. 6
·期 26
·4314-4325
·
IF 4.776
Tao Liu,Shaohua Chen,Siyi Zhang,Xidong Wu,Peina Wu,Beiping Miao,Xiang Cai
Transferrin-functionalized chitosan-graft-poly(L-lysine) dendrons (CS–PLLD–Tf) were synthesized in this work and then used to deliver the MMP-9 shRNA plasmid to HNE-1 cells for gene therapy. The obtained CS–PLLD–Tf displayed excellent gene transfection in vitro, verifying the strategy of constructing a high-efficiency gene carrier by conjugating the multiple low generation PLLDs to one molecule of CS to form a copolymer. Particularly, CS–PLLD–Tf showed much higher gene transfection efficiency than PEI-25k and CS–PLLD in the presence of serum, and more than 40% HNE-1 cells were transfected. This result led to an obvious decrease in MMP-9 protein expression and the apoptosis of HNE-1 cells as well as inhibition of the growth and invasion of HNE-1 tumors. The in vivo anti-tumor assay showed that CS–PLLD–Tf delivered the MMP-9 plasmid effectively and the tumor volume decreased more than 77% compared with the PBS control group. Moreover, CS–PLLD–Tf displayed higher bioavailability and good biocompatibility such as lower cytotoxicity, excellent blood compatibility and non-toxicity to organs, suggesting a potential application in gene therapy of tumors.
研究领域:
癌症研究
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基因治疗
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生物医学工程
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药剂学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2022
·
IF 4.369
Ying Wang,Jiyu Yang,Yu Wang,Yao Chen,Yiran Wang,Hongying Kuang,Xiaoling Feng
Polycystic ovary syndrome (PCOS) is a complex endocrine disease . Thioredoxin-interacting protein (TXNIP) promotes oxidative stress and triggers inflammation. Herein, we investigated the role and potential mechanism of TXNIP in PCOS. In a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS, we found that TXNIP was upregulated in the ovaries , especially in granulosa cells (GCs). TXNIP was also upregulated in testosterone (T)-treated GCs in vitro. Knockdown of TXNIP by lentivirus-constructed shRNA attenuated T-induced GC injury and oxidative stress, as well as inflammation and the NLRP3 inflammasome . The mechanism by which TXNIP promotes inflammation may involve TXNIP dissociation from the TXNIP-TRX complex and binding to NLRP3 to form the inflammasome. Additionally, we verified that knockdown of TXNIP ameliorated ovarian injury and inflammation in mice with DHEA-induced PCOS in vivo. Collectively, we demonstrated that TXNIP is involved in GC inflammation by promoting NLRP3 inflammasome activation in PCOS.
研究领域:
内分泌学
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生殖医学
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分子生物学
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炎症
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2018
·
IF 6.383
Feihu Wang,Qian Huang,Yun Wang,Wenjun Zhang,Ran Lin,Yanna Yu,Yuanyuan Shen,Honggang Cui,Shengrong Guo
Simultaneous inhibition of both tumor growth and metastasis is the key to treating metastatic cancer, yet the development of effective drug delivery systems represents a great challenge since multimodal therapeutic agents must be rationally combined to overcome the biological mechanisms underpinning tumor cell proliferation and invasion. In this context, we report a hybrid therapeutic nanoscale platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. In our design, we first conjugated DOX via an acid-labile linker onto gold nanorods that were pre-modified with the tumor targeting peptide RGD and a positively charged, disulfide cross-linked short polyethylenimines (DSPEI), and then incorporated shRNA through electrostatic complexation with DSPEI. We show that this “all in one” nanotherapeutic system (RDG/shRNA@DOX) can be effectively internalized through RGD-mediated endocytosis , followed by stimuli-responsive intracellular co-release of DOX and shRNA. Our in vitro experiments suggest that this multimodal system can significantly inhibit cell proliferation, angiogenesis , and invasion of metastatic MDA-MB-435 cancer cells. Systemic administration of RDG/shRNA@DOX into a metastatic mouse model led to enhanced tumor accumulation, and, most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides important insight into the rational design of therapeutic systems for the effective treatment of metastatic carcinoma. Statement of Significance The key to successfully treat metastatic cancer is the simultaneous inhibition of both tumor growth and metastasis. This represents a great challenge for the design of drug delivery systems since multimodal therapeutic agents must be rationally combined to overcome the respective biological mechanisms underpinning tumor cell proliferation and invasion. Toward this end, we developed a hybrid nanomedicine platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. We showed that this multimodal system (RDG/shRNA@DOX) enhanced tumor accumulation, led to prolonged circulation, and most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides significant insight into the rational design of therapeutic systems for the effective treatment of metastatic cancer.
研究领域:
纳米医学
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肿瘤学
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药物递送系统
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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
·
2022
·
IF 11.467
Zhen Wang,Bixi Ding,Yuanpei Zhao,Yue Han,Yu Sheng,Ling Tao,Xiangchun Shen,Jianping Zhou,Lei Jiang,Yang Ding
Increasing knowledge of drug delivery properties, tumor profiles and their relationship promotes precise administration regimens, representing a promising pattern to personalized tumor treatment. Herein, we propose a regulatory hydrogel depot toward metastatic cancer by establishing mathematical models between tumor characteristics and administration regimens. Specifically, a thermo-sensitive PLGA-PEG-PLGA polymer is introduced as injectable hydrogel matrix, of which the administration volume and frequency are manipulated elaborately according to tumor size and gel-degradation kinetics. Structurally, doxorubicin (Dox) and arginine-terminated nanoparticles containing KIAA1199 specific shRNA ( shKIAA RPDNs) are incorporated into hydrogels, thereby formulating a topical and sustained drug depot to achieve synergy treatment. For dual-targeting therapy, Dox interdicts DNA replication/transcription, and shKIAA persistently silences KIAA1199 protein to modulate aggressive phenotypes. After individual peritumoral injection, Gel/ shKIAA RPDNs/Dox demonstrates desirable distribution patterns and gel degradation kinetics with enhanced tumor penetration. Moreover, a preferable inhibition of tumor proliferation and metastasis is confirmed after twice treatment in 12 days, indicating better therapeutic efficacy with less dosage and frequency. Consequently, the controllable administration regimen inspired mathematical models of thermosensitive hydrogel provides an intelligent platform for personalized treatment to metastatic cancer.
研究领域:
肿瘤学
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药学
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生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2022
·
IF 1.798
Ning HAN,Ying SU,Mi GUO,Li YU
Diabetic retinopathy (DR) is the prevalent microvascular complication of diabetes mellitus (DM), and it may lead to permanent blindness. The previous publication has indicated that both inflammatory response and oxidative stress are critical factors involved in DR progression, however, the accurate regulatory mechanism remains to be revealed. Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), a member of the protein tyrosine phosphatase family, was reported to play a role in diabetic nephropathy, whereas its function in DR was unknown and required further exploration. The level of phosphorylated, not the total, SHP2 increased in the retinas of rats with streptozotocin injection-induced DM. Further, the intravitreal injection of SHP2 shRNA lentivirus alleviated retinal pathological changes, and inhibited inflammatory response and oxidative stress, which were accompanied with Yes-associated protein 1 (YAP1) deactivation in DR rats. Additional co-immunoprecipitation results confirmed the interaction of SHP2 and YAP1. Collectively, our data preliminarily show that DR amelioration-induced by SHP2 inhibition in rats may attribute to the deactivation of YAP1 pathway.
研究领域:
眼科学
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分子生物学
·
糖尿病研究
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细胞信号传导
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DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Weina Fan,Jian Huang,Fanglin Tian,Xin Hong,Kexin Zhu,Yuning Zhan,Xin Li,Xiangyu Wang,Xin Wang,Li Cai,Ying Xing
Alternative splicing (AS) generates protein diversity and is exploited by cancer cells to drive tumor progression and resistance to many cancer therapies, including chemotherapy. SNRPA is first identified as a spliceosome-related gene that potentially modulates resistance to platinum chemotherapy. Both the knockout or the knockdown of SNRPA via CRISPR/Cas9 and shRNA techniques can reverse the resistance of cisplatin-resistant lung adenocarcinoma (LUAD) cells to cisplatin. SNRPA overexpression enhanced the resistance of cisplatin-sensitive LUAD cells. Gene Ontology (GO) analysis reveals that SNRPA is associated with DNA damage repair. Depletion of SNRPA induced ERCC1 exon 8 skipping and reduced ERCC1–XPF complex formation, whereas SNRPA overexpression exerted the opposite effect. siRNAs targeting isoforms containing ERCC1 exon 8 [ERCC1-E8 (+)] reversed SNRPA-enhanced cisplatin resistance and DNA damage repair. Furthermore, the IGF2BP protein, an m 6 A reader, and the ELAVL1 protein, an RNA stabilizer recruited by IGF2BP1, are found to bind to the SNRPA mRNA. ELAVL1 promoted cisplatin resistance, DNA repair and ERCC1-E8 (+) expression in an SNRPA-dependent manner. In a mouse xenograft model, SNRPA- KO CRISPR enhanced the sensitivity of LUAD cells to cisplatin. Overall, this study illuminates the role of SNRPA in platinum-based drug resistance, thereby providing a novel avenue to potentially enhance chemosensitivity and improve the prognosis of patients with LUAD.
研究领域:
癌症生物学
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分子生物学
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遗传学
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药理学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Zhe Wang,Lin Qi,Yong Huang,Zheng Liu,Ruibang Wu,Yize Zhao,Hao Li,Siyi Wang,Limin Liu,Li Zhang,Ganjun Feng
Leptin, a kind of adipokine, with its receptor in which the long isoform plays a crucial role in signal transduction, has been identified in intervertebral disc (IVD) tissues, especially showing an increased expression in degenerated discs. Initially identified as a metabolic sensor, leptin has recently been found able to regulate inflammation into imbalance, which favors catabolic degradative processes, thus contributing to progressive intervertebral disc degeneration (IDD). Therefore, efficiently inhibiting the leptin pathway may provide a new strategy to treat IDD. In this study, we introduced an innovative drug delivery system (DDS) that employs stem cell membranes (SCM) to encapsulate (Zeolitic imidazolate frameworks-8) ZIF-8 nanoparticles. These nanoparticles are used to transport a plasmid containing shRNA targeting the leptin receptor (LEPR), with the aim of facilitating repair in IDD. The regenerative performances of this DDS in IDD were verified through a combination of the in vitro western blot and immunofluorescence with the in vivo radiologic examination and histological staining. The DDS demonstrated excellent cell adhesion properties and gene transfection efficiency in vitro, along with impressive treatment outcomes in vivo. Both in vitro and in vivo studies revealed that the DDS effectively reduced leptin receptor expression and alleviated the inflammatory environment, thereby promoting regeneration in degenerated IVDs. We propose that the DDS represents a promising novel approach for treating IDD and may also be beneficial for other degenerative diseases linked to leptin pathway dysfunction.
研究领域:
纳米技术
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生物医学工程
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分子生物学
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再生医学
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骨科
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2017
·
IF 5.012
Jun Tang,Hongping Miao,Bing Jiang,Qianwei Chen,Liang Tan,Yihao Tao,Jianbo Zhang,Fabao Gao,Hua Feng,Gang Zhu,Zhi Chen
Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective . However, the phenotype transformation and the way by which neuron-microglia dialogue remain unclear. We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1 + microglia secreting neurotrophic factors and restores damaged neuronal circuit. Here, we report a novel function of JWH133 in transforming the microglia CX3CR1 positive that secrete brain-derived neurotrophic factor (BDNF), which triggers neuron proliferation and neuronal restoration. Using a collagen VII-induced GMH model in rat pups postnatal day 7 (P7), we found that the drug showed robust activity in neuronal precursors. Moreover, the FA value of DTI in the internal zone revealed the positive effects of JWH133 on neural restoration. CX3CR1, a critical modulating molecule expressed in microglia, was upregulated after treatment with JWH133 and the corresponding shRNA (NM_133534.1) was used to silence the expression of CX3CR1. 3 days after treatment with JWH133, we detected reduced expression of biomarkers for neural progenitor cells (NPCs) in pups pre-injected in the lateral ventricular tissue with CX3CR1 shRNA, but not in pups injected with control shRNA. Overall, this study provides evidence that JWH133 promoted a neurotrophic phenotype of microglia (CX3CR1 + microglia), beyond merely alleviating microglial proliferation and inflammation. Moreover, JWH133 restored impaired neuronal circuit, which represent a novel therapeutic strategy following GMH in clinic.
研究领域:
神经科学
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药理学
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神经生物学
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DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2023
·Vol. 24
·期 1
·1-18
·
IF 5.8
Wu Zhuhua,Zhu Li,Nie Xinran,Liu Yingli,Zhang Xiaoju,Qi Yong
Background Obesity has been identified as a risk factor for acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the underlying mechanisms remain elusive. This study aimed to investigate the role of fatty acid synthase (FASN) in lipopolysaccharide (LPS)-induced ALI under obesity. Methods A high-fat diet-induced obese (DIO) mouse model was established and lean mice fed with regular chow diet were served as controls. LPS was intratracheally instilled to reproduce ALI in mice. In vitro, primary mouse lung endothelial cells (MLECs), treated by palmitic acid (PA) or co-cultured with 3T3-L1 adipocytes, were exposed to LPS. Chemical inhibitor C75 or shRNA targeting FASN was used for in vivo and in vitro loss-of-function studies for FASN. Results After LPS instillation, the protein levels of FASN in freshly isolated lung endothelial cells from DIO mice were significantly higher than those from lean mice. MLECs undergoing metabolic stress exhibited increased levels of FASN, decreased levels of VE-cadherin with increased p38 MAPK phosphorylation and NLRP3 expression, mitochondrial dysfunction, and impaired endothelial barrier compared with the control MLECs when exposed to LPS. However, these effects were attenuated by FASN inhibition with C75 or corresponding shRNA. In vivo, LPS-induced ALI, C75 pretreatment remarkably alleviated LPS-induced overproduction of lung inflammatory cytokines TNF-α, IL-6, and IL-1β, and lung vascular hyperpermeability in DIO mice as evidenced by increased VE-cadherin expression in lung endothelial cells and decreased lung vascular leakage. Conclusions Taken together, FASN inhibition alleviated the exacerbation of LPS-induced lung injury under obesity via rescuing lung endothelial dysfunction. Therefore, targeting FASN may be a potential therapeutic target for ameliorating LPS-induced ALI in obese individuals.
研究领域:
药理学
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免疫学
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肺科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2025
·
IF 15.4
Zeng Ke,Zhu Yuqi,Han Zhongxin,Xiong Siyi,Zhao Yan,Xiao Zilong,Xie Yingchao,Jin Shiyu,Dong Tingru,Lan Lan,Liu Weiwei,Du Yongzhong,Guan Cuiping,Yu Xiao,Song Xiuzu
NLRP3 functions as a critical intracellular danger sensor for inflammasome activation, playing a crucial role in autoimmune diseases. Vitiligo progression has been linked to NLRP3, yet its specific involvement in melanocytes of vitiligo remains poorly understood. In this study, we demonstrate that NLRP3 expression is significantly upregulated in the melanocytes of vitiligo patients and melanoma-Treg-induced vitiligo mouse model. Genetic knockout of NLRP3 effectively alleviates vitiligo progression in these mice. Our mechanistic investigations reveal that the downregulation of the E3 ligase β-TrCP1 in vitiligo melanocytes decreases K27-linked ubiquitination levels of NLRP3, which in turn weakens its interaction with the autophagy receptor NDP52. This disruption impairs the selective autophagic degradation of NLRP3, leading to hyperactivation of inflammation and pyroptosis in melanocytes, thereby accelerating vitiligo pathogenesis. Notably, melanocyte-specific knockdown of NLRP3 using lysine-proline-valine (KPV)-modified deformable liposomes (KPV-Lipos) carrying Nlrp3 shRNA significantly alleviates vitiligo development. This study elucidates the mechanism by which autophagy dysfunction mediated excessive NLRP3 inflammasome activation in melanocytes contributes to vitiligo pathogenesis, highlighting potential therapeutic strategies targeting these pathways for the treatment of vitiligo and other pigment-related skin diseases. Overview of disrupted NLRP3 autophagic degradation in vitiligo melanocytes . In healthy melanocytes, NLRP3 expression is upregulated when subjected to oxidative stress, along with an increase in the E3 ligase β-TrCP1, which enhances the K27-linked ubiquitination of NLRP3 and further strengthens its binding to the autophagy receptor protein NDP52, thus effectively suppressing the excessive inflammatory response. Whereas in the melanocytes of vitiligo patients, decreased expression of β-TrCP1 leads to downregulation of K27-linked ubiquitination in NLRP3, thus inhibiting its autophagic degradation. The persistent activation of NLRP3 in vitiligo melanocytes promotes the cleavage of pro-IL-1β and GSDMD. GSDMD-N subsequently forms pores on the cell membrane, which causes the release of IL-1β and results in melanocyte pyroptosis. In our study, we utilize KPV-Lipos with Nlrp3 shRNA to precisely knockdown NLRP3 expression in melanocytes and effectively alleviate vitiligo development, which provide a potentially promising strategy for the treatment of vitiligo. MC, melanocytes.
研究领域:
皮肤病学
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免疫学
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细胞生物学
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自身免疫性疾病
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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 NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-20
·
IF 10.2
Huang Yufen,Kou Qinjie,Su Yanrong,Lu Lu,Li Xisheng,Jiang Haiye,Gui Rong,Huang Rong,Nie Xinmin,Li Jian
Strategies to overcome toxicity and drug resistance caused by chemotherapeutic drugs for targeted therapy against hepatocellular carcinoma (HCC) are urgently needed. Previous studies revealed that high oxidored-nitro domain-containing protein 1(NOR1) expression in HCC was associated with cisplatin (DDP) resistance. Herein, a novel dual-targeting nanocarrier system AR-NADR was generated for the treatment of DDP resistance in HCC. The core of the nanocarrier system is the metal–organic frameworks (MOF) modified with nuclear location sequence (NLS), which loading with DDP and NOR1 shRNA (R). The shell is an A54 peptide inserted into the erythrocyte membrane (AR). Our results show that AR-NADR efficiently internalized by tumor cells due to its specific binding to the A54 receptors that are abundantly expressed on the surface of HCC cells and NLS peptide-mediated nuclear entry. Additionally, DDP is more likely to be released due to the degradation of Ag-MOF in the acidic tumor microenvironment. Moreover, by acting as a vector for gene delivery, AR-NADR effectively inhibits tumor drug resistance by suppressing the expression of NOR1, which induces intracellular DDP accumulation and makes cells sensitive to DDP. Finally, the anti-HCC efficacy and mechanisms of AR-NADR were systematically elucidated by a HepG2/DDP cell model as well as a tumor model. Therefore, AR-NADR constitutes a key strategy to achieve excellent gene silencing and antitumor efficacy, which provides effective gene therapy and precise treatment strategies for cisplatin resistance in HCC. Graphical Abstract
研究领域:
肿瘤学
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药学
·
分子生物学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2019
·
IF 3.829
Tao Liu,Jingzhen Li,Xidong Wu,Siyi Zhang,Zhongming Lu,Guanxue Li,Junzheng Li,Shaohua Chen
A drug and gene co-delivery system with chemotherapeutic sensibilization was prepared and used for nasopharyngeal carcinoma therapy. For this purpose, the graphene oxide (GO) was conjugated with the redox hyperbranched poly(amido amine) (HPAA) and then the targeting molecule, transferrin (Tf), was also conjugated. The obtained Tf-HPAA-GO could co-deliver docetaxel (DOC) and MMP-9 shRNA plasmid (pMMP-9) effectively and showed the targeting effect to HNE-1 cells. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency. Besides that, Tf-HPAA-GO/DOC also showed the chemotherapeutic sensibilization effect, the formulation containing HPAA segments showed much higher cytotoxicity than free DOC. Benefiting from the sensibilization effect and DOC/pMMP-9 co-delivery strategy, this Tf-HPAA-GO/DOC/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. This strategy provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization, and targeting into one single platform, which showed a promising application in cancer therapy.
研究领域:
癌症治疗
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药学
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生物材料
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分子生物学
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纳米技术
✓ 已验证
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）