BMC CANCER
·
2021
·Vol. 21
·期 1
·1-12
·
IF 4.43
Hong Xian,Li Zhi-Xuan,Hou Jie,Zhang Hui-Yu,Zhang Chun-Yan,Zhang Jian,Sun He,Pang Li-Hong,Wang Tao,Deng Zhi-Hui
Background Anterior gradient-2 (AGR2) is a proto-oncogene involved in tumorigenesis and cancer progression. AGR2, predominantly localized in the endoplasmic reticulum (ER), is also a secreted protein detected in the extracellular compartment in multiple cancers. However, the biological functions of intracellular and extracellular AGR2 remain to be elucidated. Methods Based on the biochemical structure of AGR2 protein, PANC-1 pancreatic cancer cells stably expressing ER-resident or secreted AGR2 were generated by a lentivirus-mediated stable overexpression system. The capacities of cell proliferation, migration, invasion and survival were assessed in PANC-1 stable cells. Moreover, EGFR expression and activation were determined to explore the possible mechanism of AGR2 roles in pancreatic cancer tumorigenesis. Results It was discovered that secreted AGR2, but not ER-resident AGR2, promotes cell proliferation, migration and invasion of PANC-1 cells. Moreover, the data indicated that both the ER-resident and the secreted AGR2 enhance the survival capacity of PANC-1 cells after tunicamycin-induced ER stress and gemcitabine treatment. However, EGFR expression and activation were not found to be involved in AGR2-dependent oncogenic phenotypes in PANC-1 cells. Conclusions Secreted AGR2 is predominantly involved in cell proliferation, migration and invasion in PANC-1 pancreatic cancer cells. Both secreted and ER-resident AGR2 contribute to the survival of PANC-1 cells under the challenging conditions. These findings provide insight into how different localizations of AGR2 have contributed to pancreatic cancer growth, metastasis, and drug sensitivity.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-17
·
IF 9.429
Li Qian,Chen Qiubing,Yang Xue,Zhang Yuelan,Lv Linyue,Zhang Zhuyou,Zeng Shaowei,Lv Jiaxi,Liu Sijin,Fu Bishi
Background Immune checkpoint inhibitor-mediated immunotherapy cannot be carried out on a large scale clinically due to its low universality. In recent years, cyclic guanosine monophosphate synthase/interferon gene stimulating factor (cGAS/STING)-mediated innate immune signaling pathway-mediated immunotherapy has attracted more and more attention. In addition, metabolic inhibitors also show good effects on tumor treatment, but their application is often limited because of their large first pass effect or difficult administration. Methods The particle size and potential parameters were measured by DLS. In order to determine the optimal ratio of the two drugs, we calculated the CI value of different nanoparticles through MTT experiment, and simulated their synergistic effect through Gaussian software. Then the morphology and crystal form of the best proportion of drugs were studied by TEM and XRD. The anti-tumor mechanism of composite nanoparticles was confirmed by the determination of metabolic related indexes, Q-PCR and WB. The antitumor effect and immune activation effect were comprehensively evaluated by in vivo and in vitro experiments. Results Here, we found and synthesized BCP nanoparticles ((BPA + CPI) @ PLGA NPs) which can effectively reduce the metabolism of tumor cells and inhibit cell proliferation. At the same time, the release of mitochondrial DNA (mtDNA) caused by mitochondrial metabolism disorder further activated the cGAS/STING signal pathway in Hepa1–6 cells. We found that the drug-treated Hepa1–6 cells had obvious TBK1 phosphorylation and STING dimerization. Combined with STING agonist, it could effectively promote the activation of CD8 T cells and enhanced the therapeutic effect on liver cancer. Conclusion Our results showed that PLGA nanocarrier can successfully improve the dosage forms of two metabolic inhibitors and show the effect of synergistic therapy. BCP nanoparticles can also activate the innate immunity of tumor cells and significantly enhance tumor inhibition after combined with STING agonists. This study has high reference and transformation value for the combined treatment of immunosuppression and metabolic inhibition. Graphical Abstract
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
·
2022
·Vol. 33
·期 10
·1-11
·
IF 4.727
Wei Li,Qin Shuai,Ye Yulin,Hu Jiawei,Luo Danyang,Li Yusi,Gao Yiming,Jiang Liting,Zhou Qi,Xie Xianfei,Li Ning
Cartilage is an alymphatic, avascular and non-innervated tissue. Lack of potential regenerative capacity to reconstruct chondral defect has accelerated investigation and development of new strategy for cartilage repair. We prepared a manganese ion-incorporated natupolymer-based scaffold with chitosan-gelatin by freeze-drying procedure. The scaffold was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, energy dispersive spectroscopy, compressive testing, and analysis of porosity and flexibility. Live/dead assay confirmed the good cytocompatibility of prepared scaffold on rat articular chondrocytes after 10 days and 4 weeks of culture. The manganese-loaded composite scaffold upregulated the expression of chondrogenic-related markers (Sox9, integrin, and Col II) in chondrocytes. Western blot analysis of proteins extracted from chondrocytes grown on scaffolds indicated the signaling pathways of p-Akt and p-ERK1/2 played a key role. Histological analysis following implantation of current composite scaffold loaded with chondrocytes into a rat articular cartilage defect model showed that the scaffolds promoted the formation of collagen II and cartilage repair. These findings suggested the potential of manganese-loaded scaffold to promote new cartilage formation and a promising strategy for articular cartilage engineering application.
✓ 已验证
DOI
PubMed
高影响因子
BMC Pharmacology & Toxicology
·
2022
·Vol. 23
·期 1
·1-14
·
IF 2.605
Chen Weisin,Yasen Miersalijiang,Wang Hanquan,Zhuang Chenyang,Wang Zixiang,Lu Shunyi,Jiang Libo,Lin Hong
Background Intervertebral disc degeneration results from a variety of etiologies, including inflammation and aging. Degenerated intervertebral discs feature down-regulated extracellular matrix synthesis, resulting in losing their ability to retain water and absorb compression. Celecoxib is a well-known selective cyclooxygenase-2 inhibitor for treating arthritis and relieving pain. Nevertheless, the mechanism of Celecoxib for treating inflammation-related intervertebral disc degeneration has not yet been clarified.MethodProtein synthesis was analyzed by western blot. Fluorescent probes DCFH-DA and MitoSox Red detected reactive oxygen species and were measured by flow cytometry. The activity of the kinase pathway was evaluated by protein phosphorylation. Autophagy was monitored by mRFP-GFP-LC3 transfection and LC3 analysis. Mitochondrial apoptotic proteins were analyzed by western blot and cell membrane integrity was measured by flow cytometry. The autophagic gene was silenced by siRNA.Results In this study, interleukin-1β stimulation reduced the synthesis of aggrecan, type I and II collagen and caused excessive production of reactive oxygen species. We looked for a therapeutic window of Celecoxib for nucleus pulposus cells to regain extracellular matrix synthesis and reduce oxidative stress. To look into nucleus pulposus cells in response to stimuli, enhancement of autophagy was achieved by Celecoxib, confirmed by mRFP-GFP-LC3 transfection and LC3 analysis. The mammalian target of rapamycin and a panel of downstream proteins responded to Celecoxib and propelled autophagy machinery to stabilize homeostasis. Ultimately, inhibition of autophagy by silencing autophagy protein 5 disrupted the protective effects of Celecoxib, culminating in apoptosis.Conclusion In summary, we have demonstrated a new use for the old drug Celecoxib that treats intervertebral disc degeneration by enhancing autophagy in nucleus pulposus cells and opening a door for treating other degenerative diseases.
✓ 已验证
DOI
PubMed
高影响因子
Biomaterials Research
·
2022
·Vol. 26
·期 1
·1-20
·
IF 15.863
Sun Di,Mou Shan,Chen Lifeng,Yang Jie,Wang Rongrong,Zhong Aimei,Wang Wei,Tong Jing,Wang Zhenxing,Sun Jiaming
Background Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been found to have a great potential for soft tissue repair due to various biological functions, including pro-angiogenesis and low immunogenicity. However, the low yield and heterogeneity of MSC-EVs limited their clinical transformation. This study was designed to develop a novel adipose-derived stem cell engineered nanovesicles (ADSC-NVs) with high production and explore its pro-angiogenetic effect and application in adipose tissue regeneration.Methods Adipose-derived stem cell-derived extracellular vesicles (ADSC-EVs) were isolated from an EVs-free culture medium for human ADSCs (hADSCs). ADSC-NVs were prepared by sequentially extruding ADSCs followed by iodixanol density gradient ultracentrifugation and were compared with ADSC-EVs in morphology, size distribution, protein contents and yield. The pro-angiogenetic effect of ADSC-NVs in different doses (0, 5, 20 and 80 μg/mL) in vitro was determined using transwell assay, tube formation assay, western blot and qRT-PCR. In vivo, BALB/c nude mice were administered injection of a mixture of fat granules and different dose of ADSC-NVs and grafts were harvested at 12 weeks post-transplantation for further analysis. By analyzing the weight and volume of grafts and histological evaluation, we investigated the effect of ADSC-NVs in vessel formation and adipose tissue regeneration.Results Our results showed yield of purified ADSC-NVs was approximately 20 times more than that of ADSC-EVs secreted by the same number of ADSCs. In vitro, both ADSC-NVs and ADSC-EVs exhibited a dose-dependent pro-angiogenetic effect, despite their distinct miRNA profiles. These effects of ADSC-NVs may be mediated by enriched miR-21-5p via PTEN inhibition and PI3K/p-Akt signaling activation. Furthermore, after a mixed injection of ADSC-NVs, vessel formation and adipose regeneration were observed in vivo in fat implants.Conclusion sOur study developed a potent alternative of ADSC-EVs. ADSC-NVs have a high pro-angiogenesis potential and can be used as cell-free therapeutic biomaterials in soft tissue regeneration.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-14
·
IF 10.435
Li Jiali,Li Shichao,Li Yang,Yuan Guanjie,Shen Yaqi,Peng Yang,Kong Li,Yang Conglian,Zhang Zhiping,Li Zhen
Background Immunochemotherapy is a potent anti-tumor strategy, however, how to select therapeutic drugs to enhance the combined therapeutic effect still needs to be explored. Methods and results Herein, a magnetic resonance nanoprobe (MnP@Lip) with STING (Stimulator of INterferon Genes) activation character was synthesized and co-administered with platinum-based chemotherapeutics for enhanced immunochemotherapy. MnP@Lip nanoparticles was prepared by simple fabrication process with good reproducibility, pH-sensitive drug release behavior and biocompatibility. In vitro experiments elucidated that Mn 2+ can promote the polarization of M0 and/or M2 macrophages to M1 phenotype, and promote the maturation of BMDC cells. Upon Mn 2+ treatment, the STING pathway was activated in tumor cells, mouse lung epithelial cells, and immune cells. More importantly, anti-tumor experiments in vivo proved that MnP@Lip combined with platinum-based chemotherapeutics increased T cells infiltration in the tumor microenvironment, and inhibited tumor growth in the orthotopic therapeutic and postoperative tumor models. Conclusions This kind of therapeutic strategy that combined MnP@Lip nanoparticles with platinum-based chemotherapeutics may provide a novel insight for immunochemotherapy. Graphical Abstract
✓ 已验证
DOI
PubMed
高影响因子
APOPTOSIS
·
2021
·Vol. 26
·期 1
·111-131
·
IF 4.677
Li Na,Wang JuYuan,Zang XiaoLing,Wang ZhaoYang,Zhang Tao,Zhao BaoXiang,Miao JunYing,Lin ZhaoMin
H 2 S is actual an endogenous signaling gas molecule and involved in a range of cell physiological processes. However, the mechanism of endogenous H 2 S regulating autophagy and apoptosis has not been thoroughly investigated. Here, we try to address this issue by using a H 2 S probe, (E)-2-(4-(4-(7-(diethylamino)-2-oxo-2H-chromene-3-carbonyl)-piperazin-1-yl)-styryl)-1, 3, 3-trimethyl-3H-indol-1-ium iodide (CPC), which could react with endogenous H 2 S. Herein, we reported that CPC inhibited autophagy and decreased the expression and activity of NF-E2-related factor 2 (Nrf2), then induced cell apoptosis. CPC inhibited autophagy and promoted apoptosis by inhibiting Nrf2 activation, which was H 2 S dependent. Furthermore, we found that CPC inhibited Nrf2 nucleus translocation by inhibiting glutathionylation of Kelch-like ECH-associated protein 1 (Keap1) at the Cys434 residue. CPC also inhibited various cancer cell growth, but had no effect on normal cell growth in vitro, and inhibited A549 cancer growth, but did not affect normal angiogenesis in vivo . Therefore, we not only found a new inhibitor of autophagy and Nrf2, but also suggested a novel mechanism that endogenous H 2 S could regulate autophagy, apoptosis and Nrf2 activity through regulating glutathionylation of Keap1 at the Cys434 residue.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-23
·
IF 10.435
Zhang Wei,Gong Chunai,Chen Ziqiang,Li Ming,Li Yuping,Gao Jing
Background Biomimetic nanotechnology-based RNA interference (RNAi) has been successful in improving theranostic efficacy in malignant tumors. Its integration with hybrid biomimetic membranes made of natural cell membranes fused with liposomal membranes is mutually beneficial and extends their biofunctions. However, limited research has focused on engineering such biomimetics to endow them with unique properties and functions, in particular, those essential for a “smart” drug delivery system, such as a tumor microenvironment (TME)-activated multifunctional biomimetic nanoplatform.Results Herein, we utilized an integrated hybrid nanovesicle composed of cancer cell membranes (Cm) and matrix metallopeptidase 9 (MMP-9)-switchable peptide-based charge-reversal liposome membranes (Lipm) to coat lipoic acid-modified polypeptides (LC) co-loaded with phosphoglycerate mutase 1 (PGAM1) siRNA (siPGAM1) and DTX. The nanovesicle presented a negatively charged coating (citraconic anhydride-grafted poly-l-lysine, PC) in the middle layer for pH-triggered charge conversion functionalization. The established chemotherapeutic drug (DTX) co-delivery system CLip-PC@CO-LC nanoparticles (NPs) have a particle size of ~ 193 nm and present the same surface proteins as the Cm. Confocal microscopy and flow cytometry results indicated a greater uptake of MMP-9-treated CLip-PC@CO-LC NPs compared with that of the CLip-PC@CO-LC NPs without MMP-9 pretreatment. The exposure to MMP-9 activated positively charged cell-penetrating peptides on the surface of the hybrid nanovesicles. Moreover, pH triggered membrane disruption, and redox triggered DTX and siRNA release, leading to highly potent target-gene silencing in glycolysis and chemotherapy with enhanced antiproliferation ability. The biodistribution results demonstrated that the CLip-PC@LC-DiR NPs accumulated in the tumor owing to a combination of long blood retention time, homologous targeting ability, and TME-activated characteristics. The CLip-PC@CO-LC NPs led to more effective tumor growth inhibition than the DTX and free siPGAM1 formulations.Conclusion sTME-activated cancer cell membrane-liposome integrated hybrid NPs provide an encouraging nanoplatform that combines RNAi with chemotherapy for precise treatment of non-small cell lung cancer.Graphical abstract
✓ 已验证
DOI
PubMed
高影响因子
Scientific Reports
·
2022
·Vol. 12
·期 1
·1-19
·
IF 4.996
Ilhan Recep,Üner Göklem,Yilmaz Sinem,Atalay Sahar Esra,Cayli Sevil,Erzurumlu Yalcin,Gozen Oguz,Ballar Kirmizibayrak Petek
Endoplasmic reticulum-associated degradation (ERAD) is a well-characterized mechanism of protein quality control by removal of misfolded or unfolded proteins. The tight regulation of ERAD is critical for protein homeostasis as well as lipid metabolism. Although the mechanism is complex, all ERAD branches converge on p97/VCP, a key protein in the retrotranslocation step. The multifunctionality of p97/VCP relies on its multiple binding partners, one of which is the endogenous ERAD inhibitor, SVIP (small VCP-interacting protein). As SVIP is a promising target for the regulation of ERAD, we aimed to assess its novel physiological roles. We revealed that SVIP is highly expressed in the rat adrenal gland, especially in the cortex region, at a consistently high level during postnatal development, unlike the gradual increase in expression seen in developing nerves. Steroidogenic stimulators caused a decrease in SVIP mRNA expression and increase in SVIP protein degradation in human adrenocortical H295R cells. Interestingly, silencing of SVIP diminished cortisol secretion along with downregulation of steroidogenic enzymes and proteins involved in cholesterol uptake and cholesterol biosynthesis. A certain degree of SVIP overexpression mainly increased the biosynthesis of cortisol as well as DHEA by enhancing the expression of key steroidogenic proteins, whereas exaggerated overexpression led to apoptosis, phosphorylation of eIF2α, and diminished adrenal steroid hormone biosynthesis. In conclusion, SVIP is a novel regulator of adrenal cortisol and DHEA biosynthesis, suggesting that alterations in SVIP expression levels may be involved in the deregulation of steroidogenic stimulator signaling and abnormal adrenal hormone secretion.
✓ 已验证
DOI
PubMed
高影响因子
Human Cell
·
2023
·Vol. 36
·期 3
·987-996
·
IF 4.3
Yiou Wang,Zhihong Wang,Shibai Zhu,Shanni Li,Wenwei Qian
The dysregulation of microRNAs plays a critical role in the development of rheumatoid arthritis (RA). This study aims to explore the functional significance of miR-326 in RA. The RT-qPCR results showed that miR-326 was downregulated in synovial tissues of RA patients and RA fibroblast-like synoviocytes (RA-FLS). We found that miR-326 could target and reduce the expression of inhibitor of DNA binding 1 (Id1). MTT assay and flow cytometry were conducted to explore the biological function of miR-326. Our data revealed that the upregulation of miR-326 suppressed cell proliferation and induced apoptosis in RA-FLS. In collagen-induced arthritis mice, intraarticular injection of lentivirus carrying miR-326 overexpression vectors could reduce the arthritis score and attenuate synovial inflammation and cartilage destruction. We also found that long non-coding RNA-Ewing sarcoma-associated transcript 1 (lncRNA-EWSAT1) was significantly increased in RA synovial tissues and RA-FLS. The RNA immunoprecipitation and RNA pull-down assay indicated that lncRNA-EWSAT1 directly bound and negatively regulated the expression of miR-326. Knockdown of lncRNA-EWSAT1 could upregulate miR-326 expression and attenuate its proliferation inhibition and apoptosis induction effect in RA-FLS. In conclusion, the lncRNA-EWSAT1/miR-326 axis might provide a novel therapeutic target in the treatment of RA.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-17
·
IF 10.435
Pan Xiang,Qi Yuchen,Du Zhen,He Jian,Yao Sheng,Lu Wei,Ding Kefeng,Zhou Min
Background Colorectal cancer is a common malignancy occurring in the digestive system and ranks second in cancer mortality worldwide. In colorectal cancer, hydrogen sulfide (H2S) is selectively upregulated, resulting in the further exacerbation of the disease. Therefore, the clearance of H2S and the regulation of the enzymes on the H2S pathways are of great significance for colorectal cancer therapy.Methods Here, we investigated the H2S content in various clinical tumor tissues from patients and confirmed that overproduced concentration of H2S in colorectal cancer. Accordingly, we developed an H2S-responsive nanoplatform based on zinc oxide coated virus-like silica nanoparticles (VZnO) for the therapy of colorectal cancer.Results Owing to its excellent H2S scavenging ability, VZnO could effectively reduce H2S content in colorectal cancer to prohibit the growth of CT26 and HCT116 colorectal cancer cells. Moreover, the removal of H2S in colorectal cancer also leads to tumor inhibition through activating ferroptosis, a non-apoptotic form of cell death. The biosafety-related toxicological and pathological analysis confirmed the low toxicity and high safety of VZnO in colorectal cancer treatment. Furthermore, as an H2S-responsible nanosystem, VZnO appears to have no therapeutic effect on other non H2S rich cancers, such as the 4T1 breast cancer model.Conclusion sWe anticipate that the H2S-depletion-induced ferroptosis strategy using zinc oxide-based nanomaterials would provide insights in designing nanomedicines for colorectal cancer-target theranostics and may offer clinical promise.Graphic abstract
✓ 已验证
DOI
PubMed
高影响因子
Journal of Analysis and Testing
·
2021
·Vol. 5
·期 1
·30-39
·
IF 0
Luo Rong,Xia Yunsheng
The exploration of novel fluorescent tools for subcellular analysis is of great importance for both chemical biology and biomedicine. Herein, we present an in situ self-assembly strategy for fabricating fluorescent and monodisperse CdS supraparticles (SPs), which are subsequently employed for mitochondria targeting applications. Using bovine serum albumin and linear chain cationic surfactants as templates and electrostatic modulators, respectively, CdS SPs can be well fabricated by the proposed one-step self-assembly approach in aqueous medium. In addition to high stability, favorable biocompatibility, as well as decent quantum efficiency, the as-prepared SPs have mitochondria targeting capacity due to their cationic surfactant modification. Interestingly, the localization capacity is positively correlated with the length of the cationic surfactant molecules. As the carbon chains of the cationic surfactant molecules enhance from 10 to 16 atoms, the colocalization efficiencies are correspondingly increased from 81 to 84%. Graphical abstract
✓ 已验证
DOI
危险品化学品经营许可证（带存储）