Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Yingqi Chen,Zuocheng Qiu,Xueling Hu,Tiehua Wang,Guoqing Li,Ziling Tang,Chongzhou Fang,Weibei Sheng,Jin Zhao,Fei Yu,Jian Weng,Anjaneyulu Udduttula,Geetha Manivasagam,Hui Zeng
In clinical settings, regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods, restricted bone growth medications, and a scarcity of commercial bone grafts. To treat this life-threatening issue, improved biofunctional grafts capable of properly healing critical-sized bone defects are required. In this study, we effectively created anti-fracture hydrogel systems using spongy-like metal-organic (magnesium-phosphate) coordinated chitosan-modified injectable hydrogels (CPMg) loaded with a bioinspired neobavaisoflavone (NBF) component. The CPMg-NBF hydrogels showed outstanding anti-fracture capabilities during compression testing and retained exceptional mechanical stability even after 28 d of immersion in phosphate-buffered saline. They also demonstrated prolonged and stable release profiles of Mg 2+ and NBF. Importantly, CPMg-NBF hydrogels revealed robust biphasic mineralization and were non-toxic to MC3T3-E1 cells. To better understand the underlying mechanism of Mg 2+ and NBF component, as well as their synergistic effect on osteogenesis, we investigated the expression of key osteogenic proteins in the p38 MAPK and NOTCH pathways. Our results showed that CPMg-NBF hydrogels greatly increased the expression of osteogenic proteins (Runx2, OCN, OPN, BMPS and ALP). In vivo experiments showed that the implantation of CPMg-NBF hydrogels resulted in a significant increase in new bone growth within critical-sized calvarial defects. Based on these findings, we expect that the CPMg-NBF supramolecular hydrogel has tremendous promise for use as a therapeutic biomaterial for treating critical-sized calvarial defects.
研究领域:
生物材料
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组织工程
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骨科
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生物医学工程
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药学
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产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2023
·
IF 8.8
Yang Yi,Wenzhe Li,Kefang Liu,Heng Xue,Rong Yu,Meng Zhang,Yang-Oujie Bao,Xinyuan Lai,Jingjing Fan,Yuxi Huang,Jing Wang,Xiaomeng Shi,Junhua Li,Hongping Wei,Kuanhui Xiang,Linjie Li,Rong Zhang,Xin Zhao,Xue Qiao,Hang Yang,Min Ye
Currently, human health due to corona virus disease 2019 (COVID-19) pandemic has been seriously threatened. The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19. However, the efficacy is compromised by the SARS-CoV-2 evolvement and mutation. Here we report the SARS-CoV-2 S protein receptor-binding domain (RBD) inhibitor licorice-saponin A3 (A3) could widely inhibit RBD of SARS-CoV-2 variants, including Beta, Delta, and Omicron BA.1, XBB and BQ1.1. Furthermore, A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells, with EC 50 of 1.016 μM. The mechanism was related with binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis combined with quantum mechanics/molecular mechanics (QM/MM) simulations. Interestingly, phosphoproteomics analysis and multi fluorescent immunohistochemistry (mIHC) respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 MAPK pathways and rebalancing the corresponding immune dysregulation. This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.
研究领域:
病毒学
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药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2024
·
IF 10.7
Wei Li,Qingwen Zeng,Bing Wang,Chao Lv,Haoan He,Xi Yang,Bin Cheng,Xiaoan Tao
Although oxidative stress is closely associated with tumor invasion and metastasis, its’ exact role and mechanism in the initial stage of oral cancer remain ambiguous. Glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) participates in glutathione synthesis to resolve oxidative stress. Currently, we firstly found that ASCT2 deletion caused oxidative stress in oral mucosa and promoted oral carcinogenesis induced by 4-Nitroquinoline-1-oxide (4-NQO) using transgenic mice of ASCT2 knockout in oral epithelium. Subsequently, we identified an upregulated gene Thbs1 linked to macrophage infiltration by mRNA sequencing and immunohistochemistry. Importantly, multiplex immunohistochemistry showed M1-like tumor-associated macrophages (TAMs) were enriched in cancerous area. Mechanically, targeted ASCT2 effectively curbed glutamine uptake and caused intracellular reactive oxygen species (ROS) accumulation, which upregulated Thbs1 in oral keratinocytes and then activated p38, Akt and SAPK/JNK signaling to polarize M1-like TAMs via exosome-transferred pathway. Moreover, we demonstrated M1-like TAMs promoted malignant progression of oral squamous cell carcinoma (OSCC) both in vitro and in vivo by a DOK transformed cell line induced by 4-NQO. All these results establish that oxidative stress triggered by ASCT2 deletion promotes oral carcinogenesis through Thbs1-mediated M1 polarization, and indicate that restore redox homeostasis is a new approach to prevent malignant progression of oral potentially malignant disorders.
研究领域:
癌症生物学
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免疫学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Wenbo Ge,Zhun Li,Yajun Yang,Xiwang Liu,Zhaohan Zhu,Lixia Bai,Zhe Qin,Xiao Xu,Jianyong Li,Shihong Li
Pathogenic Escherichia coli ( E. coli ) can cause intestinal diseases in humans and livestock, damage the intestinal barrier, increase systemic inflammation, and seriously threaten human health and the development of animal husbandry. In this study, we designed and synthesized a novel conjugate florfenicol sulfathiazole (FST) based on drug combination principles, and investigated its antibacterial activity in vitro and its protective effect on inflammatory response and intestinal barrier function in E. coli O78-infected mice in vivo . The results showed that FST had superior antibacterial properties and minimal cytotoxicity compared with its prodrugs as florfenicol and sulfathiazole. FST protected mice from lethal E. coli infection, reduced clinical signs of inflammation, reduced weight loss, alleviated intestinal structural damage. FST decreased the expression of inflammatory cytokines IL-1β, IL-6, TNF-α, and increased the expression of claudin-1, Occludin, and ZO-1 in the jejunum, improved the intestinal barrier function, and promoted the absorption of nutrients. FST also inhibited the expression of TLR4, MyD88, p-p65, and p-p38 in the jejunum. The study may lay the foundation for the development of FST as new drugs for intestinal inflammation and injury in enteric pathogen infection.
研究领域:
药理学
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微生物学
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免疫学
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兽医学
✓ 已验证
DOI
PubMed
高影响因子
CANCER LETTERS
·
2024
·
IF 9.1
Ying Ning,Yu Chen,Tian Tian,Xinyan Gao,Xiaolan Liu,Jia Wang,Huijun Chu,Chenyang Zhao,Yufei Yang,Ke Lei,He Ren,Zhumei Cui
Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
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IF 10.2
Shaoyin Wei,Dong Yang,Zeyu Shou,Yipiao Zhang,Shengwu Zheng,Xingjie Zan,Lianxin Li,Chunwu Zhang
Defective diabetic wound healing is a major clinical challenge, where hyperglycemia at the wound site induces excessive reactive oxygen species (ROS) which activate the MAPK pathway (particularly p38 MAPK), resulting in sustained release of inflammatory factors and cellular damage/apoptosis. Polyphenols are efficient ROS scavengers which reduce the level of inflammation at the wound site and promote wound healing, but the low bioavailability limits their biomedical application. This study developed a simple and highly efficient method for preparing proanthocyanidin (PC) capsules through hydrogen bonding and hydrophobic interactions among PC molecules. PC capsules can continuously scavenge free radicals and release proanthocyanidins, significantly enhancing their bioavailability. A single dose of PC capsules accelerates wound healing in diabetic mice by regulating the p38 MAPK signaling cascade, reducing inflammatory mediator concentration, inhibiting cell apoptosis, and remodeling the wound microenvironment. This research makes an important contribution to the field of enhancing polyphenol bioavailability for wound healing and reveals the potential of modulating the MAPK pathway for treating other inflammation and oxidative stress-related diseases.
研究领域:
药理学
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伤口愈合
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糖尿病
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炎症
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氧化应激
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信号传导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2021
·
IF 4.013
Lanqiu Zhang,Hejun Gao,Lei Yang,Tianyu Liu,Qi Zhang,Jing Xun,Caixia Li,Lihua Cui,Ximo Wang
FTY720 is an immunosuppressive agent which has been approved to treat multiple sclerosis (MS). The main object of the present study is to investigate whether FTY720 has the potential to induce the formation of neutrophil extracellular traps (NETs) in vitro. Using Sytox Green assay and fluorescence microscopy , our results showed that FTY720 trigged the NET formation. In contrast to classic NET formation induced by Phorbol 12-myristate 13-acetate (PMA), FTY720-induced NETs were detected earlier and independent of NADPH oxidase (NOX) activity. Pharmacological inhibitor experiments indicated that autophagy was also required for the NET formation induced by FTY720. Moreover, p38 and AKT inhibitor significantly suppressed the NET formation by FTY720, whereas ERK inhibitor had no effect, suggesting that FTY720-induced NETs depended on the activation of p38 and AKT. We further found that citrullination of histone H3 and peptidylarginine deiminase 4 (PAD4) did not mediated FTY720-induced NET formation. Interestingly, necroptosis signaling activation was involved in the vital NET formation by FTY720, however, plasma membrane rupture resulting from necroptosis was not a major component of NET formation described here. Collectively, these findings indicated that FTY720 could be a potential antibacterial drug to protect host against pathogen infection.
研究领域:
免疫学
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细胞生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-29
·
IF 10.6
Yu Xiao-Jun,Zhao Yuan-Ting,Abudouaini Haimiti,Zou Peng,Li Tian-Qi,Bai Xiao-Fan,Wang Shan-Xi,Guan Jian-Bin,Li Meng-wei,Wang Xiao-dong,Wang Ying-guang,Hao Ding-Jun
Methods Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1β. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action. Results CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1β, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3). Conclusion The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs. Graphical Abstract Molecular mechanism of GCA targeting CFIm25 in NP cells to promote regeneration of degenerated intervertebral disc NP
研究领域:
生物医学工程
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再生医学
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组织工程
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分子生物学
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细胞生物学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Discovery
·
2023
·Vol. 9
·期 1
·1-23
·
IF 33.5
Yin Jie,Zhao Ziming,Huang Jianzheng,Xiao Yang,Rehmutulla Mewlude,Zhang Biqiong,Zhang Zijun,Xiang Ming,Tong Qingyi,Zhang Yonghui
Acute liver failure (ALF) is a severe life-threatening disease associated with the disorder of the gut-liver axis. However, the cellular characteristics of ALF in the gut and related therapeutic targets remain unexplored. Here, we utilized the D-GALN/LPS (D/L)-induced ALF model to characterize 33,216 single-cell transcriptomes and define a mouse ALF intestinal cellular atlas. We found that unique, previously uncharacterized intestinal immune cells, including T cells, B cells, macrophages, and neutrophils, are responsive to ALF, and we identified the transcriptional profiles of these subsets during ALF. We also delineated the heterogeneity of intestinal epithelial cells (IECs) and found that ALF-induced cell cycle arrest in intestinal stem cells and activated specific enterocyte and goblet cell clusters. Notably, the most significantly altered IECs, including enterocytes, intestinal stem cells and goblet cells, had similar activation patterns closely associated with inflammation from intestinal immune activation. Furthermore, our results unveiled a common Ep300 -dependent transcriptional program that coordinates IEC activation during ALF, which was confirmed to be universal in different ALF models. Pharmacological inhibition of Ep300 with an inhibitor (SGC-CBP30) inhibited this cell-specific program, confirming that Ep300 is an effective target for alleviating ALF. Mechanistically, Ep300 inhibition restrained inflammation and oxidative stress in the dysregulated cluster of IECs through the P38-JNK pathway and corrected intestinal ecology by regulating intestinal microbial composition and metabolism, thereby protecting IECs and attenuating ALF. These findings confirm that Ep300 is a novel therapeutic target in ALF and pave the way for future pathophysiological studies on ALF.
研究领域:
肝病学
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转录组学
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免疫学
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药理学
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
Yanyan Zhu,Yameng Jiang,Lei Shi,Linying Du,Xiaodong Xu,Enxia Wang,Yong Sun,Xin Guo,Boyang Zou,Huaxin Wang,Changyuan Wang,Lidan Sun,Yuhong Zhen
7- O -Geranylquercetin (GQ) is a novel O -alkylated derivate of quercetin . In this study, we evaluated its apoptosis induction effects in human gastric cancer cell lines SGC-7901 and MGC-803 and explored the potential molecular mechanisms. The results demonstrated that GQ lowered viability of SGC-7901 and MGC-803 cells in a dose- and time-dependent manner without apparent cytotoxicity to human gastric epithelial cell line GES-1. GQ could induce apoptosis in SGC-7901 and MGC-803cells, and arrest the gastric cancer cells at G2/M phase. Mechanism study showed that GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways , subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax, and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis. In addition, Z-VAD-FMK (caspase inhibitor) could reverse GQ-induced apoptosis. SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor) could rescue GQ-induced cell death and attenuate mitochondrial signal pathway activation. Furthermore, NAC (ROS inhibitor) could rescue GQ-induced cell death, reduce ROS generation, decrease the phosphorylation of p38 and JNK, and then attenuate the activation of mitochondrial signal pathway. Taken together, GQ induces caspase-dependent apoptosis in gastric cancer cells through activating ROS-MAPK mediated mitochondrial signal pathway. This study highlights the potential use of GQ as a gastric cancer therapeutic agent.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2020
·
IF 4.679
Di Wu,Shuangqiu Li,Peixuan Li,Aimin Jiang,Ziyi Liu,Yong Zhang,Jingjing Wang,Zhengtao Yang,Zhengkai Wei
Diacetoxyscirpenol (DAS) is one kind of type A trichothecene mycotoxin which produced by Fusarium species which contaminates agricultural crops and food . DAS attracts particular attention because of the strong toxicity. Heterophil extracellular traps (HETs) is a defense mechanism in the chicken innate immune. In this study, we firstly examine the effects and molecular mechanisms of DAS on HETs release, and then investigate the immune toxicity of DAS-induced HETs on chicken liver. HETs structures were observed by immunofluorescence staining and mechanisms were investigated by fluorescence microplate and Western blot . The results showed DAS triggered HETs formation which consists of chromatin decorated with citrullinated histone 3 (citH3) and elastase . Glycolysis was confirmed to be involved in this process and the inhibitors of NADPH oxidase , ERK 1/2 , p38 MAPK-signaling pathways and glycolysis significantly decreased HETs formation. Moreover, investigation in vivo showed DAS significantly increased HETs formation in serum and DNase I (a standard degradative agent of HETs) significantly decreased the ALT and AST levels and ameliorated DAS-caused inflammatory cell infiltration of liver. In conclusion, this study proves that DAS-induced HETs formation plays an immune toxicity role in chicken liver injury and these results provide a new therapeutic target for DAS-induced liver injury in chickens.
研究领域:
兽医学
·
免疫学
·
毒理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2021
·
IF 4.86
Jie Tang,Mingrong Bei,Jia Zhu,Guangtao Xu,Deqing Chen,Xin Jin,Jianzhong Huang,Jingjian Dong,Lili Shi,Long Xu,Bo Hu
Cadmium (Cd) exposure can exert an impact on carcinogenicity of breast cancer, however, the mechanism is not fully understood in triple-negative breast cancer (TNBC). We performed a TNBC MDA-MB-231 cell model and assessed the toxic effect of Cd exposure (0, 10, 20, 50, 60, 80 μM). Cd reduced cell viability in a time- and dose-dependent manner, followed by cell cycle arrest in S phase with alterations of cyclin 1A1, cyclin 1D1 and CDK2. Lactate dehydrogenase (LDH) release, apoptosis and pyroptosis were increased, which were relieved by z-VAD. Elevated ROS and NLRP3, caspase-1, IL-1β and IL-18 were detected, which was attenuated by N-acetylcysteine. Increased bax and decreased caspase-8, caspase-9 and caspase-3 were found. gasdermin E (GSDME) was activated with cleavage of GSDME-NT, which was retarded by z-VAD. Additionally, p38 MAPK signaling pathway was activated. Our data demonstrate GSDME-activated pyroptosis in Cd toxicity, implying a potential impact on TNBC.
研究领域:
毒理学
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肿瘤学
·
细胞生物学
·
分子生物学
✓ 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）