ENVIRONMENTAL TOXICOLOGY
·
2023
·Vol. 38
·期 7
·1756-1767
·
IF 4.5
Lin Zhao,Liyuan Wang,Han Wang,Tao Xi,Sijia Liu,Yang Li,Jianping Ruan,Yongqing Huang
Fluoride induces endoplasmic reticulum (ER) stress in ameloblasts, which is responsible for enamel mineralization disorder. Fluoride induces autophagy in ameloblasts, but the molecular mechanisms through which ameloblasts respond to fluoride-induced cellular stress and autophagy remain unclear. This study investigated ER stress-induced autophagy and the regulatory role of the ER molecular chaperone GRP78 in fluoride-induced autophagy in ameloblast LS8 cells. To explore the relationship between fluoride-induced ER stress and autophagy, we assessed changes in fluoride-induced autophagy in LS8 cells following overexpression and/or silencing of the ER stress molecular chaperone GRP78. We found that autophagy induced by fluoride was further increased after GRP78 overexpression in LS8 cells. Fluoride-induced autophagy was reduced in GRP78-silenced LS8 cells. Furthermore, we found that ER stress can regulate autophagy in fluoride-treated ameloblasts (LS8 cells) and that the GRP78/IRE1/TRAF2/JNK pathway is involved in the underlying regulation. Our study suggests that ER stress plays a role in fluoride-induced damage by inducing ameloblast autophagy.
研究领域:
口腔生物学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2025
·
IF 5.7
Liying Wang,Mengxiang Tian,Bingzhi Dong,Weiqi Li,Liang Shi,Yifan Tong,Wei Chen,Xin Yu,Hongxia Xu,Bo Shen,Hong Yu
Acute pancreatitis (AP) is a common abdominal inflammatory disease, characterized by pancreatic autodigestion, acinar cell necrosis, and systemic inflammation. Currently, there is a lack of specific drugs in the treatment of AP. Traditional Chinese medicine (TCM) is an effective approach in the prevention and treatment of AP, with rheum being one of the key components in commonly used TCM formulas for treating AP. We screened emodin as the core active ingredient of rheum and developed a heparin-modified emodin carrier, EMO@ZIF-8/Heparin (HEZ), which specifically delivers emodin to the inflamed pancreatic tissue via CD44-targeted macrophage activation. The HEZ exhibited higher macrophage uptake efficiency in the inflammatory microenvironment, restored the mitochondrial membrane potential, alleviated oxidative stress, and effectively reduced the levels of cytokines in the AP cell model. Moreover, the formulation exhibited targeted enrichment and retention in the pancreas under AP conditions, blocking the systemic inflammatory amplification cascade, reducing approximately 50% of pathological damage in both pancreatic and lung tissues, decreasing the proportion of apoptotic pancreatic cells, and increasing the 15-day survival rate of AP mice from 15% to around 50%. Mechanistically, the formulation restored impaired macrophage mitochondrial function to a healthy state by inhibiting the JNK pathway. In summary, the multifunctional HEZ provides an upstream therapeutic strategy by targeting macrophages in AP, offering a novel and effective approach to potentially enhance AP treatment in the future.
研究领域:
药理学
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免疫学
·
生物材料
·
中医学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Jie Wen,Lingmao Zhao,Zhuohan Li,Chao Pi,Xianhu Feng,Peng Shi,Hongru Yang,Ligang Chen,Xiaodong Wang,Furong Liu,Yumeng Wei,Ling Zhao
Chemotherapy remains the first choice of treatment for colon cancer despite the inevitable adverse effects. Curcumin (CU) possesses antitumor activity but has poor aqueous solubility, low bioavailability, and weak activity. To address this, nine novel monocarbonyl CU analogues were designed, synthesized, and evaluated in the present study. Among them, CA8 exhibited the highest water solubility, which was approximately 2.37 × 106 times that of CU. In addition, compared with CU, its cytotoxicity on Caco-2 cells (19.2 times/48 h) was stronger. Of note, CA8 arrestedthe cell cycle of Caco-2 cells at the G2/M phase and induced apoptosis. Meanwhile, acute toxicity experiments indicated that KM mice tolerated CA8 for up to 300 mg/kg CA8 (oral administration) and 50 mg/kg CA8 (intraperitoneal injection). The oral administration of CA8 to Sprague Dawley rats exhibited higher AUC (0-t) (6.23-fold) and longer MRT (0-t) (3.35-fold) than that of CU. CA8 also inhibited the proliferation and angiogenesis of tumor cells more than CU and tegafur. Finally, CA8 may exert anti-tumor effects through the activation of JNK pathway and inhibition of AKT pathway. These results suggest that CA8 is a safe and highly effective new drug for colon cancer treatment.
研究领域:
肿瘤学
·
药理学
·
生物化学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2019
·
IF 3.743
Zhigang Guo,Hu Guozhang,Hang Wang,Zhaohui Li,Naijie Liu
Glioma is the most common form of malignant brain cancer with high mortality rate in human. Therefore, finding effective therapeutic strategy and revealing the underlying molecular mechanism is necessary. Ampelopsin (Amp), an effective component of the traditional Chinese herb of Ampelopsis grossedentata, is reported to have important biological properties, including anti-inflammatory, anti-cancer, and anti-oxidant activity; however, its effects on human glioma are poorly understood. Here, the in vitro and in vivo study was performed to investigate the anti-glioma ability of Ampelopsin. Human glioma cell lines of U251 and A172 were treated with Ampelopsin (0, 25, 50, and 100 uM) for 24 h, followed by various analysis. And human glioma xenograft models were established by injecting U251, accompanied with administration of Ampelopsin at 50 and 100 mg/kg to confirm the anti-cancer role of Ampelopsin. We found that Ampelopsin could suppress the glioma cell proliferation by modulating G1 and S phase arrest. Incubation with Ampelopsin led to the activity of Caspase-8, Caspase-9, Caspase-3 and poly (ADP-ribose) polymerases (PARP), indicating that Ampelopsin induced apoptotic response via both intrinsic and extrinsic signaling pathways. Additionally, autophagy was also observed in Ampelopsin-treated cancer cells, which is evidenced by autophagosome formation and LC3B-II accumulation. Ampelopsin-caused cancer cell death was obviously regained by apoptosis inhibitors. Further, Ampelopsin activated c-Jun N-terminal protein kinase (JNK) expression and enhanced reactive oxygen species (ROS) generation. Suppressing JNK markedly ameliorated Ampelopsin-induced apoptosis and autophagy, and ROS scavenger exhibited similar results. In vivo, Ampelopsin inhibited tumor growth and progression in mouse xenograft models. In conclusion, our findings indicated that Ampelopsin led to G1 and S phase arrest, triggered apoptosis and autophagy through potentiating ROS generation and JNK activation in human glioma cells. Thus, Ampelopsin might be a promising candidate against human glioma.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ORAL DISEASES
·
2023
·
IF 3.8
Jiaxin Lv,Qiaona Wang,Dongyu Liu,Catherine Huihan Chu,Heyang Zhou,Guoqing Li,Jin Wu,Kunzhan Cai,Chunbo Tang
Objectives Diabetes mellitus (DM) induces oxidative tissue impairment and suppresses bone formation. Some studies have shown that phytic acid has antioxidant and anti-diabetic properties. This study aimed to investigate the potential of calcium phytate (Ca-phytate) to reverse inhibited osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) in a high glucose (HG) environment and to determine the underlying mechanism. Materials and Methods hBMSCs were exposed to HG and palmitic acid to simulate DM in vitro. Osteogenic differentiation was measured using alkaline phosphatase staining and activity assay, alizarin red S staining, qRT-PCR, Western blot and immunofluorescence staining. A critical-size cranial defect model of type 2 diabetes mellitus (T2DM) rats was established to evaluate bone regeneration. A specific pathway inhibitor was used to explore whether the MAPK/JNK pathway was involved. Results Treatment with 34 μM Ca-phytate had the highest effect on osteogenic differentiation in HG. Ca-phytate improved cranial bone defect healing in T2DM rats. The long-term HG environment inhibited the activation of the MAPK/JNK signalling pathway, which was restored by Ca-phytate. Blocking the JNK pathway reduced the Ca-phytate-mediated osteogenic differentiation of hBMSCs. Conclusion Ca-phytate induced bone regeneration in vivo and reversed HG-inhibited osteogenesis of hBMSCs in vitro via the MAPK/JNK signalling pathway.
研究领域:
医学
·
细胞生物学
·
内分泌学
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DOI
PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
·
2020
·Vol. 66
·期 10
·3375-3390
·
IF 2.751
Zhang Yu,Li Xiaozhi,Li Yaoting,Li Ying,Wang Ying,Zhu Liguo,Chen Peng,Tian Zhenyi,Qiu Yun,Feng Rui,Zeng Zhirong,He Yao,Chen Baili,Zhang Shenghong,Mao Ren,Chen Minhu
Background and Aims DNA damage-regulated autophagy modulator 1 (DRAM1) is required for induction of autophagy and apoptosis. However, the influence of DRAM1 on the pathogenesis of inflammatory bowel disease (IBD) has not been explored. Methods DRAM1 expression was examined in the intestinal mucosa of patients with IBD and colons of colitis mice. We used a recombinant adeno-associated virus carrying small hairpain DRAM1 to knock down the DRAM1 gene to treat colitis in the mice. The effect of DRAM1 on autophagy and apoptosis of intestinal epithelial cells was explored. DRAM1-mediated interaction with the c-Jun N-terminal kinase (JNK) pathway was also examined. Results DRAM1 expression in the intestinal mucosa of the IBD patients was higher than that in the control participates. DRAM1 expression in the inflammatory cells in patients with Crohn’s disease (CD) was lower than that in patients with ulcerative colitis (UC). Additionally, DRAM1 expression was correlated with the Simple Endoscopic Score for CD and the Mayo endoscopic score for UC. Serum levels of DRAM1 in the IBD group were substantially higher than those in the normal group. The knockdown of DRAM1 could alleviate colitis symptoms in mice. In in vitro experiments, knocking down DRAM1 could reduce autophagy and apoptosis levels. Mechanistically, DRAM1 may participate in the regulation of these two processes by positively regulating JNK activation. Conclusions During intestinal inflammation, the upregulation of DRAM1 may promote the activation of JNK and further aggravate intestinal epithelium damage.
研究领域:
胃肠病学
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分子生物学
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免疫学
·
病理学
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产品关联
DOI
PubMed
高影响因子
Bioengineered
·
2022
·
IF 6.832
Changgui Wu,Shaohua Chen,Yang Liu,Bo Kong,Wei Yan,Tao Jiang,Hao Tian,Zhaoyi Liu,Qi Shi,Yongjun Wang,Qianqian Liang,Xiaobing Xi,Hao Xu
The study is aimed to determine the effects of cynarin (Cyn) on mice with gouty arthritis (GA) induced by monosodium urate (MSU). We measured swelling in the hind paws of mice in vivo using Vernier calipers and ultrasound. The liver, kidney, and hind paws were stained with hematoxylin-eosin, and M1 type macrophages were detected in the hind paws using anti-F4/80 and anti-iNOS antibodies. The mRNA expression of inflammatory factors in bone marrow-derived macrophages (BMDMs) and in the hind paws was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes and the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were analyzed via western blotting. Cyn was detected in vitro using Cell Counting Kit-8 (CCK-8). Cyn treatment reduced hind paw swelling and M1 macrophage infiltration, suppressed the mRNA expression of inflammatory factors, and inhibited NLRP3 inflammasome activation in vivo, in addition to inhibiting the phosphorylation of IKKa/β, p65, and c-Jun NH 2-terminal kinase (JNK). Furthermore, Cyn exerted anti-inflammatory and anti-swelling effects in mice with GA by regulating the NF-κB and JNK pathways and NLRP3 inflammasomes.
研究领域:
药理学
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免疫学
·
风湿病学
✓ 已验证
DOI
PubMed
高影响因子
iScience
·
2023
·
IF 5.8
Zhijie Zhang,Jiangzhou Shi,Qifang Wu,Zijian Zhang,Xiaoyan Liu,Anqi Ren,Guanlin Zhao,Ge Dong,Han Wu,Jiaxuan Zhao,Yuan Zhao,Jia Hu,Hui Li,Tongcun Zhang,Fuling Zhou,Haichuan Zhu
Dexamethasone (Dex) plays a critical role in T-ALL treatment, but the mechanisms of Dex resistance are poorly understood. Here, we demonstrated that the expression of JUN was regulated in Dex-resistant T-ALL cell lines and patient samples. JUN knockdown increased the sensitivity to Dex. Moreover, the survival data showed that high expression of JUN related to poor prognosis of T-ALL patients. Then, we generated dexamethasone-resistant clones and conducted RNA-seq and ATAC-seq. We demonstrated that the upregulation of JUN was most significant and regulated by JNK pathway in Dex-resistant cells. High-throughput screening showed that HIF1α inhibitors synergized with Dex could enhance Dex resistance cells death in vitro and in vivo. Additionally, JUN combined and stabilized HIF1α in Dex resistance cells. These results reveal a new mechanism of Dex resistance in T-ALL and provide experimental evidence for the potential therapeutic benefit of targeting the JNK-JUN-HIF1α axis for T-ALL treatment.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2020
·Vol. 44
·期 3
·1116-1126
·
IF 3.417
Kang An,Yuehan Zhang,Yingjiao Liu,Shengxi Yan,Zhaowei Hou,Meng Cao,Guangkuo Liu,Congcong Dong,Juncha Gao,Gaifang Liu
Current treatments for esophageal squamous cell carcinoma (ESCC) have limited efficacy. Therefore, the development of novel therapeutic targets to effectively manage the disease and boost survival rates is imperative Neferine, a natural product extracted from Nelumbo nucifera (lotus) leaves, has been revealed to inhibit the growth of hepatocarcinoma, breast cancer and lung cancer cells. However, its effect on ESCC is unknown. In the present study, it was revealed that neferine exerted anti‑proliferative effects in ESCC. It was also revealed that it triggered arrest of the G2/M phase and enhanced apoptosis of ESCC cell lines. Moreover, its ability to trigger accumulation of reactive oxygen species (ROS) and activate the c‑Jun N‑terminal kinase (JNK) pathway was demonstrated. Further study revealed how N‑acetyl cysteine (NAC), a ROS inhibitor, attenuated these effects, demonstrating that ROS and JNK inhibitors mediated a marked reversal of neferine‑triggered cell cycle arrest and apoptosis in ESCC cells. Finally, it was revealed that neferine was involved in the inhibition of Nrf2, an antioxidant factor. Collectively, these findings demonstrated the antitumor effect of neferine in ESCC, through the ROS‑mediated JNK pathway and inhibition of Nrf2, indicating its potential as a target for development of novel and effective therapeutic agents against ESCC.
研究领域:
肿瘤学
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药理学
·
细胞生物学
·
天然产物
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-15
·
IF 10.2
Pei Manman,Liu Kaiyuan,Qu Xiao,Wang Kairuo,Chen Qian,Zhang Yuanyuan,Wang Xinyue,Wang Zheng,Li Xinyao,Chen Feng,Qin Huanlong,Zhang Yang
Background The development of multidrug resistance (MDR) during postoperative chemotherapy for colorectal cancer substantially reduces therapeutic efficacy. Nanostructured drug delivery systems (NDDSs) with modifiable chemical properties are considered promising candidates as therapies for reversing MDR in colorectal cancer cells. Selenium-doped manganese phosphate (Se-MnP) nanoparticles (NPs) that can reverse drug resistance through sustained release of selenium have the potential to improve the chemotherapy effect of colorectal cancer. Results Se-MnP NPs had an organic–inorganic hybrid composition and were assembled from smaller-scale nanoclusters. Se-MnP NPs induced excessive ROS production via Se-mediated activation of the STAT3/JNK pathway and a Fenton-like reaction due to the presence of manganese ions (Mn 2+ ). Moreover, in vitro and in vivo studies demonstrated Se-MnP NPs were effective drug carriers of oxaliplatin (OX) and reversed multidrug resistance and induced caspase-mediated apoptosis in colorectal cancer cells. OX@Se-MnP NPs reversed MDR in colorectal cancer by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (e.g., ABCB1, ABCC1 and ABCG2). Finally, in vivo studies demonstrated that OX-loaded Se-MnP NPs significantly inhibited proliferation of OX-resistant HCT116 (HCT116/DR) tumor cells in nude mice. Conclusions OX@Se-MnP NPs with simple preparation and biomimetic chemical properties represent promising candidates for the treatment of colorectal cancer with MDR.
研究领域:
肿瘤学
·
纳米医学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 11
·1296
·
IF 6
Yue Liu,Chunhong Chen,Zhihui Hao,Jianzhong Shen,Shusheng Tang,Chongshan Dai
Exposure to cadmium sulfate (CdSO4) can lead to neurotoxicity. Nevertheless, the precise molecular mechanisms underlying this phenomenon remain unclear, and effective treatment strategies are scarce. This study explored the protective effects of ellagic acid (EA), a natural polyphenolic compound, against CdSO4exposure-induced neurotoxicity in HT22 cells and the underlying molecular mechanisms. Our findings demonstrated that exposure of HT22 cells to CdSO4resulted in apoptosis, which was effectively reversed by EA in a dose-dependent manner. EA supplementation also decreased reactive oxygen species (ROS) and mitochondrial ROS production, reduced malondialdehyde (MDA) levels, and restored the activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, EA supplementation at 5–20 μM significantly counteracted Cd-induced the loss of mitochondrial membrane potential and the decrease of ATP and reduced the ratio of Bax/Bcl-2 and cleaved-caspase-3 protein expression. Furthermore, EA supplementation resulted in the upregulation of Nrf2 and HO-1 protein and mRNAs while simultaneously downregulating the phosphorylation of JNK and p38 proteins. The pharmacological inhibition of c-Jun N-terminal kinase (JNK) partially attenuated the activation of the Nrf2/HO-1 pathway induced by CdSO4and exacerbated its cytotoxic effects. In conclusion, our findings suggest that ethyl acetate (EA) supplementation offers protective effects against CdSO4-induced apoptosis in HT22 cells by inhibiting oxidative stress and activating the Nrf2 signaling pathway. Furthermore, the activation of the JNK pathway appears to play a protective role in CdSO4-induced apoptosis in HT22 cells.
研究领域:
毒理学
·
药理学
·
细胞生物学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2019
·
IF 5.808
Yayun Liu,Wei Xu,Ting Zhai,Jiaojiao You,Yong Chen
Non-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro . The in vivo study was performed using male C57BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp , reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A in vivo . These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β -oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress.
研究领域:
药理学
·
肝病学
·
代谢性疾病
✓ 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）