FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Guoliang Chen,Juan Liu,Huiyun Wang,Mingxing Wang,Guixue Wang,Tingzhang Hu
SYP-3343 is a novel strobilurin fungicide with excellent and broad-spectrum antifungal activity , and its potential toxicity raises public health concerns. However, the vascular toxicity of SYP-3343 to zebrafish embryos is still not well understood. In the present study, we investigated the effects of SYP-3343 on vascular growth and its potential mechanism of action. SYP-3343 inhibited zebrafish endothelial cell (zEC) migration, altered nuclear morphology, and triggered abnormal vasculogenesis and zEC sprouting angiogenesis , resulting in angiodysplasia . RNA sequencing showed that SYP-3343 exposure altered the transcriptional levels of vascular development-related biological processes in zebrafish embryos including angiogenesis, sprouting angiogenesis, blood vessel morphogenesis , blood vessel development, and vasculature development. Whereas, the addition of NAC exerted an improvement effect on zebrafish vascular defects owing to SYP-3343 exposure. Additionally, SYP-3343 altered cell cytoskeleton and morphology, obstructed migration and viability, disrupted cell cycle progression, and depolarized mitochondrial membrane potential, as well as promoted apoptosis and reactive oxygen species (ROS) in HUVEC. SYP-3343 also caused an imbalance of the oxidation and antioxidant systems and irritated the alterations in the cell cycle- and apoptosis-related genes in HUVECs. Collectively, SYP-3343 has high cytotoxicity, possibly by up-regulating p53 and caspase3 expressions and bax/bcl-2 ratio via ROS, leading to malformed vascular development.
研究领域:
毒理学
·
发育生物学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Dan Han,Meihua Wang,Ningyu Dong,Jiaxing Zhang,Dingran Li,Xiaoling Ma,Ying Ma,Siliang Wang,Yun Zhu,Cheng Wang
Lipid nanoparticles (LNPs) hold great promise as carriers for developing drug delivery systems (DDSs) aimed at managing ischemic stroke (IS). Previous research has highlighted the vital role played by the lipid composition and biophysical characteristics of LNPs, influencing their interactions with cells and tissues. This understanding presents an opportunity to engineer LNPs tailored specifically for enhanced IS treatment. We previously introduced the innovative concept of reconstituted lipid nanoparticles (rLNPs), which not only retain the advantages of conventional LNPs but also incorporate lipids from the originating cell or tissue. Brain-derived rLNPs (B-rLNPs) exhibit significantly superior accumulation within the cerebral ischemic region when compared to liver-derived rLNPs (L-rLNPs). The homing effect of B-rLNPs was then employed to construct 3-n-butylphthalide (NBP) loaded DDS (B-rLNPs/NBP) for the treatment of IS. Our results demonstrated that compared with free NBP, B-rLNPs/NBP can significantly reduce infarct volume, neurological deficits, blood-brain barrier (BBB) leakage rate, brain water content, neutrophil infiltration, alleviate pathological structures, and improve the motor function in MCAO/R model. We also proved that B-rLNPs/NBP showed further reinforced protective effects on the same model than free NBP through the regulation of TLR4/MyD88/NF-κB (anti-inflammation) and Bax/Bcl-2 (anti-apoptosis) pathways. This study offers a promising tool towards improved IS treatment.
研究领域:
神经科学
·
药学
·
生物技术
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Haiting Liu,Guangqing Cai,Shuai Yuan,Xionghui Zhou,Rong Gui,Rong Huang
Triple-negative breast cancer (TNBC) is characterized by high malignancy and limited treatment options. Given the pressing need for more effective treatments for TNBC, this study aimed to develop platelet membrane (PM)-camouflaged silver metal–organic framework nanoparticles (PM@MOF-Ag NPs), a biomimetic nanodrug. PM@MOF-Ag NP construction involved the utilization of 2-methylimidazole and silver nitrate to prepare silver metal–organic framework (MOF-Ag) NPs. The PM@MOF-Ag NPs, due to their camouflage, possess excellent blood compatibility, immune escape ability, and a strong affinity for 4T1 tumor cells. This enhances their circulation time in vivo and promotes the aggregation of PM@MOF-Ag NPs at the 4T1 tumor site. Importantly, PM@MOF-Ag NPs demonstrated promising antitumor activity in vitro and in vivo. We further revealed that PM@MOF-Ag NPs induced tumor cell death by overproducing reactive oxygen species and promoting cell apoptosis. Moreover, PM@MOF-Ag NPs enhanced apoptosis by upregulating the ratios of Bax/Bcl-2 and cleaved caspase3/pro-caspase3. Notably, PM@MOF-Ag NPs exhibited no significant organ toxicity, whereas the administration of MOF-Ag NPs resulted in liver inflammation compared to the control group.
研究领域:
肿瘤学
·
纳米技术
·
药学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2024
·
IF 3.3
Li Guan,Yanxin Xia,Pengfei Song,Huiru Zhao,Shengjie Zhang,Wanzhen Su,Aiyun Li,Weize Li
In this paper, we investigated the anticancer effect and the mechanism of our newly synthesized bibenzyl 8Ae against human lung cancer A549 cells. Compound 8Ae could induce apoptosis by inhibiting the glycolysis in A549 cells. Hexokinase 2 (HK2), the first key enzyme in glycolysis process, was significantly down-regulated by 8Ae. Besides, compound 8Ae induced HK2 dissociated from mitochondria to cytosol, which could be induced by inhibiting the phosphorylation of Akt. In addition, 8Ae could induce mitochondrial-mediated apoptosis, and mitochondrial membrane potential (MMP) was decreased. After 8Ae treatment, the Bax/Bcl-2 ratio was increased and cytochrome c (Cyt c ) was release from mitochondria to cytosol. Molecular docking indicated that 8Ae have an interaction with HK2 by extending into acitve pockets of the protein to form stable hydrogen bonds. Additionally, 8Ae had significantly improved pharmacokinetic properties through the prediction, comparison, and analysis of the ADMET properties of 8Ae and moscatilin (MST). Taken together, 8Ae might inhibit glycolysis by stimulating the shedding of HK2 from mitochondria and promoting mitochondria-regulated apoptosis to inhibit the proliferation of A549 cells. This article provides a research basis for bibenzyl compounds as new small molecule drugs for lung cancer.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2018
·Vol. 43
·期 7
·1439-1453
·
IF 2.772
Jia Jingjing,Zhang Ting,Chi Jieshan,Liu Xiaoma,Sun Jingjing,Xie Qizhi,Peng Sijia,Li Changyan,Yi Li
CeO 2 nanoparticles (nanoceria) have been used in many studies as a powerful free radical scavenger, and LXW7, a small-molecule peptide, can specifically target the integrin αvβ3, whose neuroprotective effects have also been demonstrated. The objective of this study is to observe the neuroprotective effect and potential mechanism of CeO 2 @PAA-LXW7, a new compound that couples CeO 2 @PAA (nanoceria modified with the functional group of polyacrylic acid) with LXW7 via a series of chemical reactions, in H 2 O 2 -induced NGF-differentiated PC12 cells. We examined the effects of LXW7, CeO 2 @PAA, and CeO 2 @PAA-LXW7 on the viability of primary hippocampal neurons and found that there was no significant difference under control conditions, but increased cellular viability was observed in the case of H 2 O 2 -induced injury. We used H 2 O 2 -induced NGF-differentiated PC12 cells as the classical injury model to investigate the neuroprotective effect of CeO 2 @PAA-LXW7. In this study, LXW7, CeO 2 @PAA, and CeO 2 @PAA-LXW7 inhibit H 2 O 2 -induced oxidative stress by reducing the production of reactive oxygen species (ROS) and regulating Bax/Bcl-2, cleaved caspase-3 and mitochondrial cytochrome C (cyto C) in the apoptotic signaling pathways. We found that the levels of phosphorylation of focal adhesion kinase (FAK) and of signal transducer and activator of transcription 3 (STAT3) increased significantly in H 2 O 2 -induced NGF-differentiated PC12 cells, whereas LXW7, CeO 2 @PAA, and CeO 2 @PAA-LXW7 suppressed the increase to different degrees. Among the abovementioned changes, the inhibitory effect of CeO 2 @PAA-LXW7 on H 2 O 2 -induced changes, including the increases in the levels of p-FAK and p-STAT3, is more obvious than that of LXW7 or CeO 2 @PAA alone. In summary, these results suggest that integrin signaling participates in the regulation of apoptosis via the regulation of ROS and of the apoptosis pathway in H 2 O 2 -induced NGF-differentiated PC12 cells. LXW7, CeO 2 @PAA, and CeO 2 @PAA-LXW7 can play neuroprotective roles by counteracting the oxidative stress and apoptosis induced by H 2 O 2 in NGF-differentiated PC12 cells. CeO 2 @PAA-LXW7 exerting a more powerful synergistic effect via the conjunction of LXW7 and CeO 2 @PAA.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2022
·
IF 10.761
Huijia Mao,Yangyang Wen,Yonghui Yu,Hongyan Li,Jing Wang,Baoguo Sun
Chemodynamic therapy (CDT) is a promising tumor-specific treatment, but still suffering insufficient reactive oxygen species (ROS) levels due to its limited efficacy of Fenton/Fenton-like reaction. Polyphenol, as a natural reductant, has been applied to promote the efficacy of Fenton/Fenton-like reactions; however, its intrinsic pro-apoptosis effects was ignored. Herein, a novel CDT/polyphenol-combined strategy was designed, based on Avenanthramide C-loaded dendritic mesoporous silica (DMSN)-Au/Fe 3 O 4 nanoplatforms with folic acid modification for tumor-site targeting. For the first time, we showed that the nanocomplex (DMSNAF-AVC-FA) induced ROS production in the cytoplasm via Au/Fe 3 O 4 -mediated Fenton reactions and externally damaged the mitochondrial membrane; simultaneously, the resultant increased mitochondrial membrane permeability can facilitate the migration of AVC into mitochondrial, targeting the DDX3 pathway and impairing the electron transport chain (ETC) complexes, which significantly boosted the endogenous ROS levels inside the mitochondrial. Under the elevated oxidative stress level via both intra- and extra-mitochondrial ROS production, the maximum mitochondrial membrane permeability was achieved by up-regulation of Bax/Bcl-2, and thereby led to massive release of Cytochrome C and maximum tumor cell apoptosis via Caspase-3 pathway. As a result, the as-designed strategy achieved synergistic cytotoxicity to 4T1 tumor cells with the cell apoptosis rate of 99.12% in vitro and the tumor growth inhibition rate of 63.3% in vivo , while very minor cytotoxicity to normal cells with cell viability of 95.4%. This work evidenced that natural bioactive compounds are powerful for synergistically boosting ROS level, providing new insight for accelerating the clinical conversion progress of CDT with minimal side effects.
研究领域:
癌症治疗
·
纳米技术
·
药学
·
生物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2016
·
IF 4.32
Shan Jiang,Rongrong Zhu,Xiaolie He,Jiao Wang,Mei Wang,Yechang Qian,Shilong Wang
Curcumin (Cur) is a promising photosensitizer that could be used in photodynamic therapy. However, its poor solubility and hydrolytic instability limit its clinical use. The aim of the present study was to encapsulate Cur into solid lipid nanoparticles (SLNs) in order to improve its therapeutic activity. The Cur-loaded SLNs (Cur-SLNs) were prepared using an emulsification and low-temperature solidification method. The functions of Cur and Cur-SLNs were studied on the non-small cell lung cancer A549 cells for photodynamic therapy. The results revealed that Cur-SLNs induced ~2.27-fold toxicity higher than free Cur at a low concentration of 15 μM under light excitation, stocking more cell cycle at G2/M phase. Cur-SLNs could act as an efficient drug delivery system to increase the intracellular concentration of Cur and its accumulation in mitochondria; meanwhile, the hydrolytic stability of free Cur could be improved. Furthermore, Cur-SLNs exposed to 430 nm light could produce more reactive oxygen species to induce the disruption of mitochondrial membrane potential. Western blot analysis revealed that Cur-SLNs increased the expression of caspase-3, caspase-9 proteins and promoted the ratio of Bax/Bcl-2. Overall, the results from these studies demonstrated that the SLNs could enhance the phototoxic effects of Cur.
研究领域:
药学
·
纳米技术
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BMC CANCER
·
2023
·Vol. 23
·期 1
·1-14
·
IF 3.8
Huang Lan,Ma Buqing,Zhang Chong,Shi Jiaqi,Shen Rui,Zhang Erci,Lian Chenlei,Wang Cuifang,Liu Jieqing
Background Prostate cancer is a disease that seriously troubles men. However, there are some inevitable limitations in interventional therapy for prostate cancer patients at present, most of which are caused by low selectivity and high toxic side effects due to unclear drug targets. In this study, we identified the target protein of Curcusone C with anti-prostate cancer potential activity and verified its target and mechanism of action. Methods Click chemistry-activity based proteomics profiling (CC-ABPP) method was used to find target protein of Curcusone C against prostate cancer. Competitive CC-ABPP, drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) methods were used to verifying the target protein. Moreover, potential mechanism was validated by western blot in vitro and by he matoxylin-eosin (HE) staining, detection of apoptosis in tumor tissue (TUNEL), and immunohistochemical (IHC) in vivo. Results We found that poly(rC)-binding protein 2 (PCBP2) was the target protein of Curcusone C. In addition, Curcusone C might disrupt the Bax/Bcl-2 balance in PC-3 cells by inhibiting the expression of the target protein PCBP2, thereby inducing mitochondrial damage and activation of the mitochondrial apoptosis pathway, and ultimately inducing apoptosis of prostate cancer cells. Conclusions Curcusone C is a potential compound with anti-prostate cancer activity, and this effect occurs by targeting the PCBP2 protein, which in turn may affect the TGF/Smad signaling pathway and Bax/Bcl-2 balance. Our results laid a material and theoretical foundation for Curcusone C, to be widely used in anti-prostate cancer.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
蛋白质组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2020
·
IF 3.347
Qiongtao Song,Ying Zhao,Yanrong Yang,Xue Han,Junguo Duan
Iron overload toxicity has been implicated in retinal pigment epithelial cell injury in age-related macular degeneration. This study investigates the effects of astragaloside IV (AS-IV), a potential retinal protective agent, on the toxicity process of retinal iron overload in vivo and in vitro . AS-IV partially restored the retinal expression of rhodopsin and retinal pigment epithelium-specific 65 kDa protein, suppressed oxidative stress and inflammatory markers, and alleviated iron deposition and retinal pathological changes in vivo . Also, AS-IV inhibited the phosphorylation of p38 and ERK mitogen-activated protein kinases (MAPKs), as well as the nuclear translocation of nuclear factor-kappa B (NF-κB). Furthermore, AS-IV prevented cell death by decreasing the ratio of Bax/Bcl-2, caspase-3, and cleaved caspase-3 expression in vitro . Although there are no chelation effects between AS-IV and iron, AS-IV can reduce intracellular iron by regulating iron-handling proteins in ARPE-19 cells (Cav1.2, divalent metal transporter-1, transferrin receptor 1 , and heavy-chain ferritin). In conclusion, the results show that AS-IV has significant protective effects against retinal iron overload toxicity and suggest that iron regulation and the inhibition of MAPKs and NF-κB activation might be mechanisms underlying the effects of AS-IV.
研究领域:
眼科学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2021
·
IF 4.221
Dan Liu,Ye Cheng,Zhipeng Tang,Xueying Mei,Xiangyu Cao,Jianli Liu
Acrolein is a hazardous air pollutant for humans and is responsible for many pulmonary diseases, but the underlying mechanisms have not been completely elucidated. This work is focused on the genotoxicity effects of human bronchial epithelial (BEAS-2B) cells induced by acrolein (20, 40, 80 μM). The molecular mechanism was investigated base on DNA damage and mitochondrial apoptosis pathways. The results showed that after exposure to acrolein, the cell viability, glutathione (GSH) of BEAS-2B cells were reduced. Reactive oxygen species (ROS) level significantly increased, accompanied by increased levels of DNA damage-related indicators 8-hydroxy-2 deoxyguanosine (8−OHdG), DNA content of comet tail (Tail DNA%), olive tail moment (OTM), and nucleus morphology. Cell arrested at the G2/M phase. Then, the DNA damage response (DDR) signaling pathway (Ataxia-telangiectasia-mutated (ATM) and Rad-3-related (ATR)/Chk1 and ATM/Chk2) and the consequent cell cycle checkpoints were activated. The expression of γ-H2AX was significantly increased, indicating that acrolein induced DNA double-strand breaks. Molecular docking assay showed that acrolein bound to DNA in a spontaneous process. Moreover, mitochondrial apoptosis pathway involved in apoptosis, mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) content of BEAS-2B cells were significantly reduced, and the apoptosis rate was significantly increased. The protein expression of Bax/Bcl-2 and Cleaved Caspase-3 were increased, and JNK signaling pathway was activated. All the results indicated that acrolein induced DNA damage, activated DDR and mitochondrial apoptosis pathways, which might be the pivotal factors to mediate cytotoxicity in BEAS-2B cells.
研究领域:
细胞生物学
·
分子生物学
·
毒理学
·
环境健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF INVESTIGATIVE SURGERY
·
2019
·
IF 1.642
Damu Lin,Hongqiang Wu,Zongwei Zhou,Zhenyu Tao,Tanghong Jia,Weiyang Gao
Background The therapeutics used to promote perforator flap survival function induces vascular regeneration and inhibit apoptosis. The present study aimed to explore the potential mechanism of the angiogenesis effects of Ginkgolide B (GB) in perforator flaps. Methods: A total of 72 rats were divided into three groups and treated with saline, GB, or GB + tunicamycin (TM; ER stress activator) for seven consecutive days, respectively. Apoptosis was assayed by determining the Bax/Bcl-2 ratio and caspase-3 level. Endoplasmic reticulum (ER) stress markers (CHOP, GRP78, and caspase-12) were detected by Western blot analysis. Oxidative stress was assessed by measuring the superoxide dismutase activity (SOD) and malondialdehyde (MDA), heme oxygenase-1(HO-1), and nuclear factor erythroid-2-related factor 2 (Nrf2) mRNA levels in the flaps. The percentage flap survival area and blood flow were assessed on postoperative day (POD) 7. Angiogenesis was visualized by hematoxylin and eosin and CD34 staining on POD 7. Results: GB increased the survival of perforator flaps, the flap survival area of GB, GB + TM, and control groups was 90.83 ± 1.93%, 70.93 ± 4.13%, and 62.97 ± 6.50%. GB decreased the Bax/Bcl-2 ratio and caspase-3 level. ER stress-related proteins were downregulated by GB. GB also decreased the MDA level and increased SOD activity, HO-1 and Nrf2 mRNA levels in the flaps. Further, GB induced regeneration of vascular vessels in comparison with saline or GB + TM. Conclusions: GB increased angiogenesis and alleviated oxidative stress by inhibiting ER stress, which increased the survival of perforator flaps. In contrast, GB + TM alleviated angiogenesis and induced oxidative stress by activating ER stress and decreasing the survival of perforator flaps.
研究领域:
药理学
·
外科学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2021
·Vol. 46
·期 3
·1295-1307
·
IF 3.591
Zhi-Gang Yin,Xiong-Wei Liu,Hui-Juan Wang,Min Zhang,Xiong-Li Liu,Ying Zhou
A highly efficient synthesis of structurally diverse ortho-acylphenol–diindolylmethane hybrids 3 using carboxylic acid-activated chromones as versatile synthetic building blocks is reported here for the first time, through 1,4-nucleophilic addition and followed by a decarboxylation and pyrone ring opening reaction process. The newly synthesized compounds were evaluated for their in vitro anticancer activity, and most of the compounds displayed good anticancer activities against four tested tumor cells (A549, PC-3, NCI-H1299, Caco-2). Among these compounds, compound 3t displayed the most potent and broad-spectrum anti-proliferative inhibition against the tested cell lines, especially A549 cells, and was more potent than arundine and cisplatin drugs, and had selectivity in cancer cells compared to MRC-5 and HK-2 normal cells. Preliminary mechanism studies showed that compound 3t exerted an anti-tumor effect in A549 cells by inhibiting the proliferation, colony formation and migration of A549 cells, and inducing cycle arrest at the G0/G1 phase and apoptosis. Furthermore, treatment of A549 cells with compound 3t caused increased ROS content and induced MMP collapse; western blot analysis showed that the expression level of p53 was significantly increased; Bax/Bcl-2 ratio and Cyt c were increased, and caspase-9, -3, and PARP were cleaved. These studies showed that compound 3t could induce apoptosis of A549 cells through the mitochondrial pathway, which was related to the activation of p53 and the generation of ROS. Thus, our results indicate that compound 3t may be used as a promising skeleton for the development of new anti-tumour drugs.
研究领域:
药物化学
·
肿瘤学
·
药学
·
细胞生物学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）