BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2020
·
IF 1.863
Yuanguo Xiong,Hao Lu,Hanlin Xu
Hepatic fibrosis (HF) is a common disease, with currently no available treatment. Galangin, a natural flavonoid extracted from Alpinia officinaruim Hance, has multiple effects demonstrated in previous studies. The aim of the present study was to explore the anti-fibrogenic effect of galangin in vitro, and research its potential molecular mechanisms. LX-2 cells were chosen as an in vitro HF model, and were treated with galangin in different concentrations. Cell viability was analyzed using Cell Counting Kit-8 (CCK-8) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis was measured using flow cytometry, and the anti-fibrogenic effect of galangin was determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunofluorescence, and western blotting. The results show that the proliferation of LX-2 cells was efficiently inhibited by galangin, and apoptosis was induced in a dose-dependent manner. Both the mRNA and protein expression of α-SMA and collagen I were markedly downregulated. Galangin also inhibited the PI3K/Akt and Wnt/β-catenin signaling pathways and increased the Bax/Bcl-2 ratio. The results of this study suggest that galangin has an anti-fibrogenic effect and may represent a promising agent in the treatment of hepatic fibrosis.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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DOI
PubMed
高影响因子
EXPERIMENTAL PHYSIOLOGY
·
2021
·Vol. 106
·期 4
·983-993
·
IF 2.969
Changfeng Shan,Ronghua Wang,Shuai Wang,Zongmeng Zhang,Chaofeng Xing,Wenbin Feng,Zhenggang Zhao,Sujin Zhou,Allan Zijian Zhao,Yunping Mu,Fanghong Li
New Findings What is the central question of this study? What is the protective benefit of n −3 polyunsaturated fatty acids (PUFAs) on liver fibrosis and what are the relevant signalling pathways in a transgenic mouse model overexpressing the mfat-1 enzyme? What is the main finding and its importance? n −3 PUFA elevation strongly prevented carbon tetrachloride (CCl 4 )-induced hepatic damage and inhibited the activation of hepatic stellate cells. n −3 PUFAs suppressed CCl 4 -induced activation of mTOR, elevated Bcl-2 expression, and reduced Bax level, suggesting that n −3 PUFAs can render strong protective effects against liver fibrosis and point to the potential of mfat-1 gene therapy as a treatment modality. Liver fibrosis is a reversible wound healing response with excessive accumulation of extracellular matrix proteins. It is a globally prevalent disease with ultimately severe pathological consequences. However, very few current clinical therapeutic options are available. Nutritional addition of n −3 polyunsaturated fatty acids (PUFAs) can delay and lessen the development of liver fibrosis. Herein, this study examined the protective benefit of n −3 PUFAs on liver fibrosis and the relevant signalling pathways using a transgenic mouse model overexpressing the mfat-1 enzyme that converts n −6 to n −3 PUFAs. Male C57BL/6 wild-type and mfat-1 transgenic mice were administered carbon tetrachloride (CCl 4 ) or control corn oil by intraperitoneal injection. Blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were subsequently measured. CCl 4 -induced hepatic damage and fibrosis were assessed using haematoxylin–eosin and Masson's trichrome staining. Western blot assays were used to detect and quantify fibrosis-related proteins and mechanistic target of rapamycin (mTOR) and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) signalling components. The direct effect of docosahexaenoic acid (DHA) on primary hepatic stellate cells (HSCs) was also investigated in a co-culture experiment. n −3 PUFAs, as a result of mfat-1 activity, had a strong protective effect on liver fibrosis. The elevation of ALT and AST induced by CCl 4 was significantly lessened in the mfat-1 mice. Histological determination revealed the protective effects of n −3 PUFAs on liver inflammation and collagen deposition. Co-incubation with DHA reduced the expression of profibrogenic factors in the primary HSCs. Moreover, mfat-1 transgenic mice showed significant reduction of proteins that are involved in mTOR and Bcl-2/Bax signalling pathways. Collectively, these results suggest that n −3 PUFA elevation strongly prevents CCl 4 -induced hepatic damage by directly inhibiting the activation of HSCs and regulating the basal activity of the mTOR and Bcl-2/Bax signalling pathways. Gene therapy applying mfat-1 and elevating n −3 PUFAs represents a promising treatment strategy to prevent liver fibrosis.
研究领域:
肝病学
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分子生物学
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药理学
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营养学
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DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2017
·
IF 4.164
Aili Suo,Junmin Qian,Minghui Xu,Weijun Xu,Yaping Zhang,Yu Yao
Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a single nanovehicle has emerged as a promising combination therapy approach to treating cancers because of their synergistic effect. Nanocarrier delivery systems with low cytotoxicity and high efficiency are needed for such a purpose. In this study, a novel folate-conjugated PEGylated cationic triblock copolymer, poly(acrylhydrazine)- block -poly(3-dimethylaminopropyl methacrylamide)- block -poly(acrylhydrazine) (PAH- b -PDMAPMA- b -PAH), was synthesized and evaluated as a stimuli-sensitive vehicle for the targeted co-delivery of doxorubicin (DOX) and Bcl-2 siRNA into breast cancer MCF-7 cells. The synthetic process of the PEGylated triblock copolymer involved sequential reversible addition-fragmentation chain transfer polymerization, PEGylation and removal of tert -butoxy carbamate protecting groups. Folate-conjugated and/or -unconjugated poly(ethylene glycol) segments were grafted onto PAH- b -PDMAPMA- b -PAH via a reduction-sensitive disulfide linkage. The synthetic polymers were characterized by 1 H NMR and gel permeation chromatography. The PEGylated triblock copolymer could chemically conjugate DOX onto PAH blocks via pH-responsive hydrazone bonds and simultaneously complex negatively charged Bcl-2 siRNA with cationic PDMAPMA blocks through electrostatic interactions at N/P ratios ≥ 32:1 to form multifunctional nanomicelleplexes. The nanomicelleplexes exhibited spherical shape, possessed a positively charged surface with a zeta potential of + 22.5 mV and had a desirable and uniform particle size of 187 nm. In vitro release studies revealed that the nanomicelleplexes could release DOX and Bcl-2 siRNA in a reduction and pH dual-sensitive manner and the payload release was significantly enhanced in a reductive acidic environment mimicking the endosomes/lysosomes of cancer cells compared to under physiology conditions. Furthermore, the release of both DOX and siRNA was found to follow Higuchi kinetic model. Confocal laser scanning microscopy, flow cytometry and MTT analyses confirmed that, compared with folate-undecorated nanomicelleplexes, folate-decorated nanomicelleplexes could more effectively co-deliver DOX and Bcl-2 siRNA into MCF-7 cells and showed a stronger cell-killing effect. The pristine PEGylated triblock copolymer exhibited good cytocompatibility. Moreover, co-delivery of DOX and Bcl-2 siRNA achieved a significant synergistic antitumor efficacy. These findings suggested that the folate-decorated PEGylated cationic triblock copolymer might be a promising vehicle for targeted intracellular co-delivery of DOX and siRNA in MCF-7 cells, representing a potential clinical combination therapy for breast cancer treatment.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Yuehuang Wu,Min Zhou,Ruimiao Lin,Lixue Yu,Xiaokun Zhang,Jingjing Xie
Combination of chemotherapeutics with polypeptide/protein drugs has been demonstrated to be an effective approach for treatment against cancer multidrug resistance. However, due to the low biostability and weak cell penetrating ability of biomacromolecules, intracellular delivery and release of biomacromolecules in a spatiotemporally controllable manner in target sites in vivo face great challenges, and synergistic effects will not be achieved as expected just by simple drug combination. Here, we conceived an inspired strategy to combat the drug-resistant tumors by fabricating multiarm PEG-gated large pore-sized mesoporous silica nanoparticles for the Bcl-2-functional-converting peptide (denoted as N9@M-CA∼8P) payload and controlled release and realizing synergistic effects with celastrol integration at a low dosage as a curative sensitizer. Our results demonstrated that the N9 peptide could be pH-responsively released from the macropores of the M-CA∼8P nanosystem both in simulated physiological environments and in cancer cells and at tumor sites. Biosafe and enhanced therapeutic outcomes (90% tumor inhibition) were obtained by combination of the N9@M-CA∼8P nanosystem with celastrol coordinatively inducing mitochondrion-mediated cell apoptosis in resistant cancer cell lines and in the corresponding xenografted mice models. Overall, this study provides convincing evidence for effective and safe resistant cancer treatment through a stimulus-responsive biomacromolecule nanosystem combined with a low dosage of a natural compound.
研究领域:
纳米医学
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癌症研究
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药学
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生物技术
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材料科学
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产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2024
·Vol. 191
·期 2
·1-12
·
IF 5.3
Wang Xiaoying,Yuan Wei,Kuang Yijing,Chen Xuyuan,Wang Xiaoning,Zhang Xiaoyu
A ratiometric electrochemical immunosensor is proposed for simultaneous detection of cellular-myelocytomatosis oncoprotein (C-myc) and B-cell lymphoma 2 (Bcl-2) via the potential-resolved strategy. It relied on multi-role co-loaded alloy composites (CLACs) and poly(3,4-ethylenedioxythiophene) (PEDOT)-graphene oxide (GO)-multiwalled carbon nanotubes (MWCNTs) (PGM) modified electrodes. CLACs with good catalytic and enzyme-like properties were synthesized in one step by loading tetramethylbenzidine (TMB) or methylene blue (MB) into Pt-Pd alloy and used as label materials. After immunological reactions, CLACs showed distinguishable dual differential pulse voltammetry signals at − 0.26 V and 0.38 V, corresponding to C-myc and Bcl-2, and the PGM had an electrochemical signal at 1.2 V, which could be used as a reference signal to construct a ratiometric sensor. CLACs had a satisfactory synergistic effect with the PGM, and eventually achieved quadruple signal amplification. Thus, benefiting from multiple magnification and ratiometric self-calibration functions, sensitive detections of C-myc and Bcl-2 were achieved, with detection limits as low as 0.5 and 2.5 pg mL −1 , respectively. Additionally, when the designed method was applied to blood samples from lymphoma patients, results consistent with the ELISA kit were obtained. This will open avenues for constructing multiple protein detection sensors. Graphical abstract
研究领域:
生物分析化学
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电化学
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生物传感器
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癌症诊断
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纳米材料
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免疫传感
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分析化学
✓ 已验证
DOI
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Zhiqiang Zhang,Qinglong Wang,Haibo Zhang,Shengchao Wang,Xia Ma,Hui Wang
Mitophagy is a distinct physiological process that can have beneficial or deleterious effects in particular tissues. Prior research suggests that mitophagic activity can be triggered by CaO2-PM-CsPbBr3 QDs, yet the specific role that mitophagy plays in hepatic injury induced by CaO2-PM-CsPbBr3 QDs has yet to be established. Accordingly, in this study a series of mouse model- and cell-based experiments were performed that revealed the ability of CaO2-PM-CsPbBr3 QDs to activate mitophagic activity. Golm1 was upregulated in response to CaO2-PM-CsPbBr3 QDs treatment, and overexpressing Golm1 induced autophagic flux in the murine liver and hepatocytes, whereas knocking down Golm1 had the opposite effect. CaO2-PM-CsPbBr3 QDs were also able to Golm1 expression, in turn promoting the degradation of P53 and decreasing the half-life of this protein. Overexpressing Golm1 was sufficient to suppress the apoptotic death of hepatocytes in vitro and in vivo, whereas the knockdown of Golm1 had the opposite effect. The ability of Golm1 to promote p53-mediated autophagy was found to be associated with the disruption of Beclin-1 binding to Bcl-2, and the Golm1 N-terminal domain was determined to be required for p53 interactions, inducing autophagic activity in a manner independent of helicase activity or RNA binding. Together, these results indicate that inhibiting Golm1 can promote p53-dependent autophagy via disrupting Beclin-1 binding to Bcl-2, highlighting a novel approach to mitigating liver injury induced by CaO2-PM-CsPbBr3 QDs.
研究领域:
细胞生物学
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分子生物学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Song Chen,Yujie Ren,Peng Duan
Lung cancer still remains a leading cause of cancer mortality in the world. Obatoclax mesylate (OM), a B cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) family antagonist, is a potential antitumor drug. However, its poor aqueous solubility restricts its clinical application. Although these inherent defects, nanotechnology can be used to improve the solubility and tumor target of OM, promoting its antitumor efficiency. In the present study, the poly(lactic-coglycolic acid) (PLGA) was used and combined with red blood-cell membrane (RBCm) to explore if OM-loaded RBCm nanoparticles could improve the antitumor efficacy of OM for the treatment of lung cancer with relatively lower side effects compared with the free OM. The good physicochemical stability of the prepared RBCm-OM/PLGA nanoparticles was confirmed, and the optimal size of 153 nm was screened out, along with sustained drug release behavior. We found that RBCm-OM/PLGA nanoparticles effectively reduced the proliferation of lung cancer cells. Additionally, RBCm-OM/PLGA nanoparticles considerably induced apoptosis in lung cancer cells by reducing Bcl-2 expression levels, accompanied with the improved Cyto-c releases in cytoplasm and Caspase-3 activation. Mitochondrial membrane potential was also obviously impaired in lung cancer cells incubated with RBCm-OM/PLGA nanoparticles. Compared with free OM, RBCm-OM/PLGA nanoparticles could greatly prolong the drug circulation time in vivo and upgraded the drug concentration accumulated in tumor tissue. Furthermore, RBCm-OM/PLGA nanoparticles exerted stronger antitumor efficacy in vivo against lung cancer progression with superior safety. Therefore, RBCm-OM/PLGA nanoparticles provided new potential for lung cancer therapy with the improved safety and therapeutic effect.
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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生物医学工程
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Zhemeng Zhao,Bin Hu,Danfeng Zhang,Xinyue Cui,Wen Ding,Tongshuai Wang,Jingyi Wang,Ziyi Guo,Yingtang Zhou,Shige Wang,Jiaming Guo
Ionizing radiation (IR) injuries are featured as acute radiation syndrome (ARS) and localized combined radiation-wound injury (CRWI). While scavenging reactive oxygen species (ROS) is a key strategy for mitigating IR-induced damage, the development of effective marine natural biomaterials for treatment remains rare and challenging. In this study, we engineered cuttlefish melanin nanoparticles (CMNs) and incorporated them into a poly (vinyl alcohol) (PVA) and sodium alginate (SA) matrix, enabling the in situ synthesis of PVA/SA@CMNs (PS@CMNs) hydrogels with multifaceted therapeutic benefits. CMNs pretreatment significantly alleviated radiation-induced damage in ARS models, particularly by protecting the hematopoietic and immune systems. Furthermore, PS@CMNs hydrogels exhibited exceptional antioxidant, photothermal antibacterial, and biodegradable properties than CMNs. Upon near-infrared laser irradiation, these hydrogels accelerated the healing of bacteria-infected CRWI. The therapeutic mechanism involves the regulation of apoptosis-related proteins, including Bax and Bcl-2, effectively inhibiting the apoptotic process. This study highlights the dual-action potential of CMNs and PS@CMNs hydrogels in mitigating radiation damage and promoting wound healing, offering a promising marine biomaterial-based approach for radiation protection and regenerative medicine.
研究领域:
放射生物学
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生物材料学
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再生医学
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产品关联
DOI
高影响因子
Molecular Medicine Reports
·
2016
·Vol. 14
·期 1
·904-910
·
IF 1.559
Liandi Xie,Yang Wu,Zongjing Fan,Yang Liu,Jixiang Zeng
In the present study, the mechanisms associated with the Astragalus polysaccharide (APS)-mediated protection of human cardiac microvascular endothelial cells (HCMEC) against hypoxia/reoxygenation (HR) injury were investigated. Pretreatment of HCMECs with APS at various concentrations was performed prior to Na2S2O4-induced HR injury. Subsequently, cell viability and apoptosis were measured by MTT and Hoechst assays, respectively. The viability of HCMECs was reduced by Na2S2O4 and apoptosis was enhanced; however, cell viability was observed to be increased by APS via inhibition of apoptosis. Additionally, intracellular reactive oxygen species (ROS), Ca2+, nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), B‑cell lymphoma‑2 (Bcl‑2), Bcl‑2 associated X protein (Bax) and caspase‑3 were measured using detection kits or western blot analysis. In HCMECs with HR injury, the levels of ROS and Ca2+, MDA and Bax expression levels, and the activity of caspase‑3 were elevated. By contrast, the level of NO, the protein expression levels of SOD, Bcl‑2 and PI3K, and the phosphorylation of AKT were decreased. However, compared with the HR group, the effects of HR injury were significantly reduced by APS, with APS providing a protective effect on HCMECs, particularly at higher doses. The current study concluded that APS protects HCMECs from Na2S2O4‑induced HR injury by reducing the levels of ROS, Ca2+, MDA and Bax, inhibiting the activity of caspase‑3, and enhancing the levels of NO, SOD, Bcl‑2, PI3K and phosphorylated AKT. These results may provide an insight into the clinical application of APS and novel therapeutic strategies for HR injury.
研究领域:
心血管研究
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2022
·
IF 3.715
Xiaohui Xia,Shuai Wang,Lirong Wu,Guoxing Li,Kaiwen Hou,Anyong Yu,Zhao Yang
Background Intracerebral hemorrhage (ICH) is a serious disease with high mortality and morbidity, and effective treatment is limited. A large amount of evidence suggests that the inflammatory response contributes to secondary brain damage following ICH. TIPE2 is an essential negative regulator of both innate and adaptive immunity, and depletion of TIPE2 causes inflammatory disease. However, the possible role of TIPE2 following ICH has not been reported. Methods In this study, we investigated TIPE2 levels and inflammation in microglia treated with erythrocyte lysate in vitro. In addition, we analyzed the role of Bcl-2/Bax/cleaved caspase-3 apoptotic pathways in ICH mice. Furthermore, we observed proinflammatory cytokine production, BBB disruption, cerebral water content and neurological damage in ICH mice. Results We found that TIPE2 levels were significantly decreased in erythrocyte lysate-treated microglia compared to control microglia.Upregulation of TIPE2 decreased microglia activation and cytokine production and accelerated brain damage in ICH mice. Furthermore, upregulation of TIPE2 decreased the higher ratio of Blc-2/Bax and increased cleaved caspase-3 levels in ICH mice. In addition, upregulation of TIPE2 attenuated proinflammatory cytokine production, BBB disruption, and severe brain inflammation after ICH. Conclusion These results demonstrated that TIPE2 was negatively correlated with the pathogenesis of ICH, which prevented brain injury and attenuated deleterious inflammatory responses following ICH. TIPE2 might serve as a novel target for ICH therapy.
研究领域:
神经科学
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分子生物学
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病理学
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药理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Shaojie Zhang,Renjie Gao,Baocong Ding,Junhao Li,Tanggan Wang,Jiaheng Chen,Chong Li,Yukun Jiao,Lijun Song
Combining selenium nanoparticles (SeNPs) with bioactive polysaccharides is one of the effective ways to overcome the shortcomings of SeNPs and polysaccharide and obtain novel antitumor drug candidates. In this study, a heteropolysaccharide (MTP70) with moderate antihepatoma activity was isolated from the stems of Marsdenia tenacissima (Roxb.) Wight et Arn. To further improve the antihepatoma activity of MTP70 and the application of SeNPs, a novel stable nanoparticle (MTP-SeNP) was designed and fabricated. MTP-SeNPs (Se content of 8.25 %) were characterized as monodisperse spherical nanoparticles (50 nm) with MTP70 wrapped on the surface of the SeNPs by the formation of C O⋯Se bonds and possessed high stability and good dispersion in water for almost a month. In addition, MTP-SeNPs showed higher inhibitory effect compared with MTP70. MTP-SeNPs could effectively inhibit the proliferation, invasion, and metastasis of HePG2 cells by inducing apoptosis and arresting the cell cycle at the S phase, which were closely related to the activation of the Bax/Bcl-2/Caspases and p-21/Akt/Cyclin A2 signaling pathways. Our results provide a theoretical basis for further development and application of M. tenacissima polysaccharide, and show that MTP-SeNPs could be explored as a promising anti-hepatoma agent in the pharmaceutical and biomedical industries.
研究领域:
药理学
·
纳米技术
·
肿瘤学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2014
·
IF 5.684
Junmin Qian,Minghui Xu,Aili Suo,Weijun Xu,Ting Liu,Xuefeng Liu,Yu Yao,Hongjie Wang
To minimize the side effects and enhance the efficiency of chemotherapy, a novel folate-decorated hydrophilic cationic star-block terpolymer , [poly( l -glutamic acid γ-hydrazide)- b -poly(N,N-dimethylaminopropyl methacrylamide)] 3 - g -poly(ethylene glycol) ((PGAH- b -PDMAPMA) 3 - g -PEG), with disulfide linkages between the PEG and PDMAPMA blocks, was developed for targeted co-delivery of doxorubicin and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The terpolymer was synthesized by a combination of ring-opening polymerization, reversible addition–fragmentation chain transfer polymerization, PEGylation and hydrazinolysis. The chemical structures of the polymers were confirmed by 1 H-NMR analysis. The terpolymer could conjugate doxorubicin via an acid-labile hydrazone linkage and simultaneously efficiently complex siRNA through electrostatic interaction at N/P ratios of ⩾4:1 to form “two-in-one” nanomicelleplexes, which displayed a spherical shape and had an average size of 101.3 nm. The doxorubicin loading efficiency and content were 61.0 and 13.23%, respectively. The cytotoxicity, drug release profile, targeting ability, cellular uptake and intracellular distribution of the nanomicelleplexes were evaluated in vitro. We found that the release behaviors of doxorubicin and siRNA had a pH/reduction dual dependency. They were released faster under reductive acidic conditions (pH 5.0, glutathione : 10 mM) than under physiological conditions (pH 7.4). The folate-decorated nanomicelleplexes could deliver doxorubicin and Bcl-2 siRNA more efficiently into the same MCF-7 cell and exhibited a higher cytotoxicity than non-targeted nanomicelleplexes. These results indicate that the terpolymer could act as an efficient vehicle for targeted intracellular co-delivery of doxorubicin and therapeutic siRNA in cancer therapy.
研究领域:
药学
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纳米技术
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癌症治疗
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高分子化学
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生物医学工程
✓ 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）