Neuroscience Bulletin
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2022
·Vol. 38
·期 12
·1457-1475
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IF 5.271
Li Qiang,Ru Xufang,Yang Yang,Zhao Hengli,Qu Jie,Chen Weixiang,Pan Pengyu,Ruan Huaizhen,Li Chaojun,Chen Yujie,Feng Hua
Insufficient remyelination due to impaired oligodendrocyte precursor cell (OPC) differentiation and maturation is strongly associated with irreversible white matter injury (WMI) and neurological deficits. We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2 (LCN2) in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1 (EGR1) as the key signals contributing to LCN2-mediated insufficient OPC remyelination. In LCN-knockdown and OPC EGR1 conditional-knockout mice, we discovered enhanced OPC differentiation in developing and injured white matter (WM); consistent with this, the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical, acute WMI due to subarachnoid hemorrhage and typical, chronic WMI due to multiple sclerosis. This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.
研究领域:
神经科学
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分子生物学
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细胞生物学
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神经病学
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DOI
PubMed
高影响因子
Clinical and Experimental Nephrology
·
2022
·Vol. 26
·期 7
·630-639
·
IF 2.617
Xia Yangyang,Wan Cheng,Zhang Qingyan,Wang Hengjin,Feng Yuan,Jiang Chunming
Background Peritoneal fibrosis (PF) is caused by epithelial-mesenchymal transdifferentiation (EMT) in the peritoneum under high glucose (HG) conditions. The study aimed to explored the role of Insulin-like growth factor 1 receptor (IGF-1R) in the regulation of EMT in human peritoneal mesothelial cells (HPMCs). Methods We used HG peritoneal dialysis fluid (PDF) to induce in vivo PF in mice, and treated HPMCs with HG in vitro to stimulate EMT. Results In the mice, the higher the glucose concentration in the dialysate, the more obvious the peritoneal tissue thickening and the more that collagen was deposited. The in vitro study indicated that the expression of IGF-1R, α-SMA, vimentin was upregulated, while the expression of occludin, ZO-1, and E-cadherin was downregulated in HPMCs under HG and IGF-1R overexpression conditions. Conversely, the expression of IGF-1R, α-SMA, and vimentin was downregulated, while the expression of occludin, ZO-1, and E-cadherin was upregulated in IGF-1R-underexpressed HPMCs under HG conditions. The cell migration abilities were increased, while the cell adhesion abilities were reduced in HPMCs under HG and IGF-1R overexpression conditions. In contrast, cell migration abilities were reduced, while cell adhesion abilities were increased in IGF-1Runderexpressed HPMCs under HG conditions. Conclusions Targeting at IGF-1R may provide novel insights into the prevention and treatment of PF.
研究领域:
肾病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-15
·
IF 9.429
Jiang Zengxin,Wang Hao,Zhang Zeng,Pan Jianfeng,Yuan Hengfeng
Targeting cartilage is a promising strategy for the treatment of osteoarthritis, and various delivery vehicles were developed to assist the therapeutic agents into cartilage. However, the underlying biomechanisms and potential bioactivities remain oversimplified. Inspired by oxidative stress in the pathogenesis of osteoarthritis, we firstly testified the antioxidant capacity of a synthetic small molecule compound, oltipraz (OL), to the chondrocytes treated by IL-1β. Then a functional reactive oxygen species (ROS) responsive nanocarrier, mesoporous silica nanoparticles (MSN) modified with methoxy polyethylene glycol-thioketal, was constructed. In vitro biomolecular results showed that compared with OL alone, MSN-OL could significantly activate Nrf2/HO-1 signaling pathway, which exhibited better ROS-scavenging proficiency and greater anti-apoptotic ability to protect mitochondrial membrane potential of chondrocytes. Further bioinformatics analysis revealed that MSN-OL suppressed clusters of genes associated with extracellular matrix organization, cell apoptosis and cellular response to oxidative stress. Animal experiments further confirmed the great cartilage-protecting ability of MSN-OL through upregulating the expression of Nrf2/HO-1 signaling pathway without obvious toxicity. In summary, this study provided a delivery system through ROS-responsive regulation of the therapeutic agents into chondrocytes of the cartilage, and confirmed the exact biological mechanisms of this innovative strategy.
研究领域:
药理学
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纳米技术
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骨科
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生物医学工程
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DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-8
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IF 4.259
Guo Dongsheng,Liu Haikun,Ruzi Aynisahan,Gao Ge,Nasir Abbas,Liu Yanli,Yang Fan,Wu Feima,Xu Guosheng,Li Yin-xiong
Congenital hyperinsulinism (CHI) is a rare genetic disorder characterized by excess insulin secretion, which results in hypoglycemia. Mutation of sulfonylurea receptor 1 (SUR1), encoded by the ABCC8 gene, is the main cause of CHI. Here, we captured the phenotype of excess insulin secretion through pancreatic differentiation of ABCC8 -deficient stem cells generated by the CRISPR/Cas9 system. ABCC8- deficient insulin-producing cells secreted higher insulin than their wild-type counterparts, and the excess insulin secretion was rescued by nifedipine, octreotide and nicorandil. Further, we tested the role of SUR1 in response to different potassium levels and found that dysfunction of SUR1 decreased the insulin secretion rate in low and high potassium environments. Hence, pancreatic differentiation of ABCC8- deficient cells recapitulated the CHI disease phenotype in vitro , which represents an attractive model to further elucidate the function of SUR1 and to develop and screen for novel therapeutic drugs.
研究领域:
遗传学
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干细胞研究
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
Scientific Reports
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2017
·
IF 4.259
Cong Xie,Tong-Meng Yan,Jia-Mei Chen,Xiao-Yan Li,Juan Zou,Li-Jun Zhu,Lin-Lin Lu,Ying Wang,Fu-Yuan Zhou,Zhong-Qiu Liu,Ming Hu
This study aims to determine whether enzyme activities are correlated with protein amounts and mRNA expression levels of five major human sulfotransferase (SULT) enzymes in 10 matched pericarcinomatous and hepatocellular carcinoma liver samples. The MRM UHPLC-MS/MS method, Western blot and RT-PCR were used along with SULT activity measurement using probe substrates. The LC-MS/MS method was specific for all five tested SULTs, whereas Western blot was specific for only two isoforms. The activities of SULT1A1, SULT1B1, SULT1E1 and SULT2A1 in 9 of 10 samples showed a significant decrease in tumor tissues relative to matched pericarcinomatous tissues, whereas the activities of SULT1A3 in 7 of 10 samples increased. The turnover numbers of SULTs did not change, except for SULT1A1. A generally high degree of correlations was observed between SULT activities and protein amounts (r 2 ≥ 0.59 except one), whereas a low degree of correlations was observed between SULT activities and mRNA expression levels (r 2 ≤ 0.48 except one). HCC reduced the SULT activities via impaired protein amounts. LC-MS/MS quantification of SULTs is highly reliable measurement of SULT activities, and may be adopted for implementing precision medicine with respect to drugs mainly metabolized by SULTs in healthy and HCC patients.
研究领域:
药理学
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分子生物学
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肿瘤学
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临床化学
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DOI
PubMed
高影响因子
HISTOCHEMISTRY AND CELL BIOLOGY
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2021
·Vol. 156
·期 1
·47-58
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IF 4.304
Sun Yuchuan,Li Hong,Chen Qiufang,Luo Qing,Song Guanbin
The survival of cancer stem cells is usually limited to a specific tumor microenvironment, and this microenvironment plays a vital role in the development of tumors. The mechanical properties of the microenvironment differ in different regions of solid tumors. However, in solid tumors, whether the distribution of cancer stem cells relates to the mechanical microenvironment of different regions is still unclear. In this study, we undertook a biophysical and biochemical assessment of the changes in the mechanical properties of liver tissue during the progression of liver cancer and explored the distribution of liver cancer stem cells in liver cancer tissues. Our analysis confirmed previous observations that the stiffness of liver tissue gradually increased with the progress of fibrosis. In liver cancer tissues, we found obvious mechanical heterogeneity: the core of the tumor was soft, the invasive front tissue was the hardest, and the para-cancer tissue was in an intermediate state. Interestingly, the greatest number of liver cancer stem cells was found in the invasive front part of the tumor. We finally established that stroma stiffness correlated with the number of liver cancer stem cells. These findings indicate that the distribution of liver cancer stem cells correlates with the mechanical heterogeneity of liver cancer tissue. This result provides a theoretical basis for the development of targeted therapies against the mechanical microenvironment of liver cancer stem cells.
研究领域:
肿瘤学
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生物物理学
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细胞生物学
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DOI
PubMed
高影响因子
ONCOGENE
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2021
·Vol. 40
·期 44
·6273-6283
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IF 9.867
Liu Zundong,Sang Xiaolin,Wang Min,Liu Yichao,Liu Jiao,Wang Xuefei,Liu Pixu,Cheng Hailing
Complete blockade of the HER2 protein itself and HER signaling network is critical to achieving effective HER2-targeted therapies. Despite the success of HER2-targeted therapies, the diseases will relapse in a significant fraction of patients with HER2 + breast cancers. How to improve the therapeutic efficacy of existing HER2-targeted agents remains an unmet clinical need. Here, we uncover a role of Melatonin in diminishing HER2-mediated signaling by destruction of HER2 protein. Mechanistically, Melatonin treatment attenuated the protective effect of the HSP90 chaperone complex on its client protein HER2, triggering ubiquitylation and subsequent endocytic lysosomal degradation of HER2. The inhibitory effect of Melatonin on HER2 signaling substantially enhanced the cytotoxic effects of the pan-HER inhibitor Neratinib in HER2 + breast cancer cells. Lastly, we demonstrate that dual inhibition of HER2 by combined use of Melatonin and Neratinib effectively blocked the growth of HER2 + breast tumor xenografts in vivo. Our findings shed light on the potential use of Melatonin in a novel dual HER2 blockade strategy for HER2 + breast cancer treatment.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Scientific Reports
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2021
·Vol. 11
·期 1
·1-12
·
IF 4.38
Chen Chang,Huang Xiansheng,Zhu Wenqiang,Ding Chen,Huang Piaopiao,Li Rong
Hyperalgesia has become a major problem restricting the clinical application of tooth bleaching. We hypothesized that transient receptor potential ankyrin 1 (TRPA1), a pain conduction tunnel, plays a role in tooth hyperalgesia and inflammation after bleaching. Dental pulp stem cells were seeded on the dentin side of the disc, which was cut from the premolar buccal tissue, with 15% (90 min) or 40% (3 × 15 min) bleaching gel applied on the enamel side, and treated with or without a TRPA1 inhibitor. The bleaching gel stimulated intracellular reactive oxygen species, Ca 2+ , ATP, and extracellular ATP in a dose-dependent manner, and increased the mRNA and protein levels of hyperalgesia (TRPA1 and PANX1) and inflammation (TNFα and IL6) factors. This increment was adversely affected by TRPA1 inhibitor. In animal study, the protein levels of TRPA1 ( P = 0.0006 ), PANX1 ( P < 0.0001 ), and proliferation factors [PCNA ( P < 0.0001 ) and Caspase 3 ( P = 0.0066 )] increased significantly after treated rat incisors with 15% and 40% bleaching gels as detected by immunohistochemistry. These results show that TRPA1 plays a critical role in sensitivity and inflammation after tooth bleaching, providing a solid foundation for further research on reducing the complications of tooth bleaching.
研究领域:
牙科
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Applied Biological Chemistry
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2022
·Vol. 65
·期 1
·1-12
·
IF 3.206
Zhang Yifan,Shen Jinhuang,Ma Xinhua,Yao Mingshuang,Zhang Yonghong,Cao Dairong
Acanthus ilicifolius var. xiamenensis (Acanthaceae), a mangrove found in southeastern China, is an herb with strong antiinflammatory property. Phytochemical study of the mangrove showed that the plant has a high content of phenylethanol glycoside acteoside (AC). In this research, the anti-inflammatory activity of acteoside on dextran sodium sulphate (DSS)-mediated mouse ulcerative colitis model were studied. For DSS- mediated colitis in mice, AC can reduce weight loss and DAI score in UC mice, suppress colon shortening and alleviate colon pathological injury. Moreover, AC treatment notably up-regulates IL-10, down-regulates the levels of IL-1β and TNF-α, and inhibits the protein expression of JAK2/STAT3, NF-κB p65, IKKα/β and IKB of colon. In addition, after AC treatment, the level of MDA and NO in colonic tissue were remarkably decreased, while the levels of GSH, SOD, and Nrf2 and HO-1 protein expression levels were significantly increased. These results indicate that AC can activate the Nrf2 signaling pathway by inhibiting the JAK/STAT, iNOS/eNOS and NF-κB signaling cascades, enhance the intestinal barrier function, and effectively reduce DSS-induced UC in mice.
研究领域:
药理学
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免疫学
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分子生物学
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DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-20
·
IF 9.429
Deng Han,Shang Wenting,Wang Kun,Guo Kunxiong,Liu Yu,Tian Jie,Fang Chihua
Despite advancements in diagnostic methods and therapeutic strategies, the mortality rate of hepatocellular carcinoma (HCC) remains as high as its incidence rate. Most liver cancers are detected in the advanced stages, when treatment options are limited. Small HCC is difficult to diagnose and is often overlooked by current imaging methods because of the complexity of the liver environment, especially in cirrhotic livers. In the present study, we developed a tumor “cruise missile”, mesoporous Fe 3 O 4 -containing glucose oxidase-conjugated GPC3 peptide nanoparticles (FGP NPs). It was designed to enhance the accuracy of small HCC visualization to 85.7% using combined ultrasound/photoacoustic imaging in complex liver environment, which facilitated sequential catalytic targeted therapy for small HCC. In a carcinogen-induced mouse HCC model, FGP NPs could be used to accurately diagnose HCC in a liver cirrhosis background as well as distinguish HCC nodules from other abnormal liver nodules, such as cirrhosis nodules and necrotic nodules, by dynamic contrast-enhanced photoacoustic imaging. In a mouse xenograft HCC model, highly reactive oxygen species were formed by sequential catalytic reactions, which promoted HCC cell apoptosis, significantly increasing the survival of the model mice. The present study provides a basis for the precise detection and elimination of small HCCs in the complex liver environment. Graphical Abstract
研究领域:
癌症生物学
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纳米技术
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医学成像
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治疗学
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DOI
PubMed
高影响因子
Discover Oncology
·
2025
·Vol. 17
·期 1
·1
·
IF 2.9
Li Mengyan,Dai Litao,Jiang Min,Lv Yuanyuan,Zhang Yahao,Wang Yuqi,Ma Yuqing
Objective All-trans retinoic acid (ATRA) has demonstrated great potential in cancer treatment; however, the molecular mechanism for the anti‐tumour effects of Cellular retinoic acid-binding protein 2 (CRABP2) and ATRA in oesophageal squamous cell carcinoma (ESCC) remains unclear. Methods A strategy of transfecting KYSE-150 cells with vectors or CRABP2 overexpression was applied in this study. Changes in cell proliferation, migration, invasion and apoptosis in OE-NC, OE-CRABP2, OE-NC + ATRA and OE-CRABP2 + ATRA groups were observed. The location of CRABP2 with ATRA and the expression of key proteins that may be involved were detected. The volume and weight of subcutaneous grafted tumours in nude mice were compared in vivo, cell morphology was observed through haematoxylin and eosin (HE) staining, and cell apoptosis was detected using TUNEL staining. Results We determined that, in vitro, CRABP2 combined with ATRA best inhibited the proliferation, migration, invasion and cell cycle of ESCC and promoted its apoptosis. Oxidative stress, the mitochondrial pathway, p53 and the NF-κB pathway may be involved in the synergistic inhibitory effect of CRABP2 and ATRA. In vivo, tumour volume in the OE-CRABP2 + ATRA group was the smallest and tumour growth was the slowest. The HE results demonstrated improved cell differentiation in the OE-CRAB2 + ATRA group, and TUNEL staining revealed that CRABP2 and ATRA had the strongest promoting effect on cell apoptosis, with the degree of cell apoptosis the greatest with the participation of ATRA. Conclusion The combination of CRABP2 overexpression and ATRA synergistically inhibits ESCC progression. All‐trans retinoic acid may be a candidate therapy for ESCC, and CRABP2 overexpression could enhance the efficacy of ATRA treatment.
研究领域:
肿瘤学
·
分子生物学
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癌症研究
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2025
·Vol. 24
·期 1
·6
·
IF 8.9
Yang Xinyi,Ning Tingting,Zhang Wanru,Hou Songyuan,Su Jiayi,Li Wenkun,Wu Jing
Background Gastric microbiota dysbiosis is closely linked to chronic inflammation and carcinogenesis. Fusobacterium nucleatum ( Fn ), an opportunistic gastrointestinal pathogen, is implicated in perturbing the immune system and form an inflammatory microenvironment that fuels the occurrence and progression of gastric cancer (GC). However, the underlying mechanisms remain elusive. We aimd to investigate the impacts of Fn on GC cells and the crosstalk between GC cells and mast cells (MCs). Methods Fn abundance and MC infiltration were assessed in clinical GC tissues. Cell-based functional experiments, including wound healing, transwell, and ELISA, were performed using conditioned medium-based co-culture systems to explore how Fn influenced GC cell migration and the crosstalk with MC. A murine lung metastasis model was employed to evaluate Fn -driven metastasis and the effects of metronidazole and Reparixin. Results We showed that Fn and MCs were enriched and positively correlated in clinical GC tissues compared to paracancerous tissues. Fn and MCs exhibited tumor-promoting properties by facilitating GC cell migration. Besides, Fn and GC cells can recruit MCs and facilitate its activation. This crosstalk between GC cells and MCs was further enhanced by Fn , thereby amplifying this positive feedback loop between them. The production of CXCL8 in response to Fn stimulation was a significant mediator. Suppression of CXCL8 in GC cells weakened Fn ’s promoting effects on GC cell migration, MC recruitment and activation. Similarly, knocking down CXCL8 in MCs reversed the Fn -induced feedback effect of MCs on the highly invasive phenotype of GC cells. Mechanistically, the exoprotein Gbp of Fn activated CypA-NF-κB pathway in both GC cells and MCs, leading to the upregulation of CXCL8 expression. In addition, the in vivo assays substantiated Fn ’s ability to enhance tumor progression by facilitating cell migration, upregulating CXCL8 expression, and inducing MC infiltration and activation. However, these effects were reversed by metronidazole, a highly Fn -susceptible antibiotic, and Reparixin. Conclusions In summary, this study suggests that Fn contributes to GC progression by promoting tumor cell migration, MCs recruitment and activation. Simultaneously, the enhanced CXCL8-mediated crosstalk between GC cells and MCs plays a vital role in the pro-cancer effect of Fn.
研究领域:
肿瘤学
·
微生物组学
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免疫肿瘤学
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分子肿瘤学
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炎症与癌症
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信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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