CURRENT MOLECULAR MEDICINE
·
2020
·Vol. 20
·期 4
·307-317
·
IF 1.6
Yang Yuan,Huang Jin,Li Jianzhong,Yang Huansheng,Yin Yulong
Background: Butyric acid (BT), a short-chain fatty acid, is the preferred colonocyte energy source. The effects of BT on the differentiation, proliferation, and apoptosis of small intestinal epithelial cells of piglets and its underlying mechanisms have not been fully elucidated.
Methods: In this study, it was found that 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells. BT at 0.5 mM or higher concentrations significantly impaired cell viability in a dose- and time-dependent manner. In addition, BT at high concentrations inhibited
the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase. Results: Our results demonstrated that BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production. BT at high concentrations
inhibited cell autophagy associated with increased lysosome formation. It was found that BT-reduced IPEC-J2 cell viability could be attenuated by p38 MAPK inhibitor SB202190. Moreover, SB202190 attenuated BT-increased p38 MAPK target DDIT3 mRNA level and V-ATPase mRNA level that were responsible
for normal acidic lysosomes. Conclusion: In conclusion, 1) at 0.2-0.4 mM, BT promotes the differentiation of IPEC-J2 cells; 2) BT at 0.5 mM or higher concentrations induces cell apoptosis via the p38 MAPK pathway; 3) BT inhibits cells autophagy and promotes lysosome formation at high
concentrations.
研究领域:
细胞生物学
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分子生物学
·
动物生理学
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DOI
PubMed
高影响因子
JOURNAL OF ALZHEIMERS DISEASE
·
2025
·
IF 3.1
Wenqiang Zhang,Fei Teng,Xifa Lan,Peihui Liu,Aiming Wang,Fan Zhang,Zhiqiang Cui,Jingwei Guan,Xiaohong Sun
BackgroundThe involvement of microglia is likely to be pivotal in the pathogenesis of Alzheimer's disease (AD) by modulating the deposition of amyloid-β (Aβ) plaques. The deletion of Dedicator of cytokinesis 8 (DOCK8) has a protective effect in mouse with neurodegenerative diseases.ObjectiveTo explore the underlying mechanism of DOCK8 in AD.MethodsIn present study, we first the detected the expression of DOCK8 in the hippocampal tissue of APP/PS1 mice. Then, the expression of DOCK8 was knocked down in the hippocampal tissue of APP/PS1 mice, and the effects of DOCK8 down-regulation on cognitive function, the microglia migration around Aβ plaques, and the cell division cycle 42 (Cdc42)/p38 mitogen-activated protein kinase (MAPK) signaling pathway were detected. Next, the effects of DOCK8 knockdown on Aβ-induced migration and activation of BV-2 cells as well as the MAPK signaling pathway were detected. Finally, the transcriptional regulation of DOCK by transcription factor 3 (ATF3) was detected by a dual luciferase reporter assay.ResultsDOCK8 expression exerts a significant upregulation in the hippocampus of APP/PS1 mice. However, following the DOCK8 knockdown, there was a significant recovery in the results of the behavioral tests and a notable reduction in microglial expression. Moreover, the high expression of DOCK8 mediated by ATF3 successfully triggered the Cdc42/p38 MAPK signaling pathway, thereby enhancing the migration and recruitment of microglia towards senile plaques, accelerating the production of Aβ plaques.ConclusionsATF3-mediated high expression of DOCK8 accelerates the production of Aβ plaques, and participates in the pathogenesis of AD.
研究领域:
神经科学
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分子生物学
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遗传学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2019
·
IF 4.067
Peihai Cao,Yiqun Xia,Wei He,Tingting Zhang,Lin Hong,Peisen Zheng,Xin Shen,Guang Liang,Ri Cui,Peng Zou
Colon cancer is a malignant type of cancer with high prevalence and is one of the primary causes of cancer-related deaths. Oxaliplatin plays a significant role in the treatment of cancer, but the application of oxaliplatin is restricted due to its toxic side effects and drug resistance in clinical practice. Therefore, there is an urgent need for new strategies that can synergize with oxaliplatin for confronting colon cancer. Alantolactone (ALT), a natural sesquiterpene lactone, possesses antitumor properties in a number of cancer cell lines. In the present study, we investigated how ALT acts synergistically with oxaliplatin on human colorectal cancer HCT116 and RKO cells in vitro and in vivo . We observed that ALT strengthened the effect of oxaliplatin-induced growth restrain and apoptosis in HCT116 and RKO cells. It is through a mechanism concerning remarkable accumulation of intracellular reactive oxygen species (ROS) and activation of JNK and p38 MAPK signaling pathways. These changes ultimately induced apoptosis of HCT116 and RKO cells. Pretreatment of cells with the ROS reversal agent NAC significantly blocked the apoptosis induced by the combination treatment, and suppressed expression of JNK and p38 phosphorylation in HCT116 and RKO cells. In the xenograft model, the combination therapy displayed stronger antitumor activity compared with single agents. Immunohistochemistry of subsequent treatment tumors showed a significant decrease in proliferation as compared to either of the treatments alone. These results suggest that the combination treatment with ALT and oxaliplatin may become a potential therapeutic strategy for colon cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Yuanqiao Ma,Xiaoxiao Xu,Hang Wu,Changbo Li,Peijie Zhong,Zejin Liu,Chuang Ma,Wenhua Liu,Chenyu Wang,Yijie Zhang,Junpeng Wang
Ivermectin has been proposed as a potential anti-inflammatory drug in addition to its antiparasitic activity. Here we investigated the potential role of ivermectin in the pathogenesis of acute lung injury (ALI) using the lipopolysaccharide (LPS)- or bleomycin (BLM)-induced mice models. Male C57BL/6 mice were given ivermectin orally every day for the remainder of the experiment at doses of 1 or 2 mg/kg after 24 h of LPS or BLM treatment. Ivermectin reversed severe lung injury caused by LPS or BLM challenge, including mortality, changes in diffuse ground-glass and consolidation shadows on lung CT imaging, lung histopathological scores, lung wet/dry ratio, and protein content in the bronchoalveolar lavage fluid (BALF). Furthermore, ivermectin also reduced total lung BALF inflammatory cells, infiltrating neutrophils, myeloperoxidase activity, and plasma TNF-α and IL-6 levels in mice treated with LPS or BLM. Finally, the mechanism study showed that LPS or BLM administration increased JNK, Erk1/2, and p38 MAPK phosphorylation while decreasing IκBα expression, an inhibitor of NF-κB. However, ivermectin increased IκBα expression but blocked elevated phosphorylated JNK and p38 MAPK, not Erk1/2, in both ALI mice. These findings suggested that ivermectin may alleviate ALI caused by LPS or BLM in mice, partly via lowering the inflammatory response, which is mediated at least by the inhibition of MAPK and NF-κB signaling. Collectively, ivermectin might be used to treat acute lung injury/acute respiratory distress syndrome.
研究领域:
药理学
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免疫学
·
呼吸病学
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DOI
PubMed
高影响因子
Journal of Natural Medicines
·
2017
·Vol. 72
·期 2
·390-398
·
IF 1.982
Lu Jianrao,Yi Yang,Pan Ronghua,Zhang Chuanfu,Han Haiyan,Chen Jie,Liu Wenrui
Renal ischemia reperfusion injury (RIRI) refers to the irreversible damage for renal function when blood perfusion is recovered after ischemia for an extended period, which is common in clinical surgeries and has been regarded as a major risk for acute renal failures (ARF) that is accompanied with unimaginably high morbidity and mortality. Hypoxia during ischemia followed by reoxygenation via reperfusion serves as a major event contributing to cell apoptosis, which has been widely accepted as the vital pathogenesis in RIRI. Preventing apoptosis in renal tubular epithelial cell has been considered as effective method for blocking RIRI. In this paper, we established a hypoxia/reoxygenation (H/R) injury model in human proximal tubular epithelial HK-2 cells. Here, we found increased SPHK1 levels in H/R injured HK-2 cells, which could be significantly down regulated after berberine treatment. Berberine has been reported to exert a protective effect on H/R-induced apoptosis of HK-2 cells. So, in our present study, we planned to investigate whether SPHK1 participated in the anti-apoptosis process of berberine in H/R injured HK-2 cells. Our study confirmed the protective effect of berberine against H/R-induced apoptosis in HK-2 cells through promoting cells viability, inhibiting cells apoptosis, and down-regulating p-P38, caspase-3, caspase-9 as well as SPHK1, while up regulating the ratio of Bcl-2/Bax. However, SPHK1 overexpression in HK-2 cells induced severe apoptosis, which can be significantly ameliorated with additional berberine treatment. We concluded that berberine could remarkably prevent H/R-induced apoptosis in HK-2 cells through down-regulating SPHK1 expression levels, and the mechanisms included the suppression of p38 MAPK activation and mitochondrial stress pathways.
研究领域:
肾病学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2023
·Vol. 43
·期 6
·913-928
·
IF 3.3
Hongmei Chang,Li Li,Yaxin Deng,Guanling Song,Yan Wang
Titanium dioxide nanoparticles (nano-TiO 2 ) is one of the most widely used and produced nanomaterials. Studies have demonstrated that nano-TiO 2 could induce hepatotoxicity through oxidative stress, and lycopene has strong antioxidant capacity. The present study aimed to explore if lycopene protects the liver of mice from nano-TiO 2 damage. Ninety-six ICR mice were randomly divided into eight groups. They were control group, nano-TiO 2 -treated group (50 mg/kg BW), lycopene-treated groups (5, 20, and 40 mg/kg BW), and 50 mg/kg BW nano-TiO 2 - and lycopene-co-treated groups (nano-TiO 2 + 5 mg/kg BW of lycopene, nano-TiO 2 + 20 mg/kg BW of lycopene, nano-TiO 2 + 40 mg/kg BW of lycopene). After treated by gavage for 30 days, the histopathology of the liver was observed. Liver function was evaluated using changes in serum biochemical indicators of the liver (AST, ALT, ALP); and the level of ROS was indirectly reflected by the level of SOD, GSH-Px, MDA, GSH, and T-AOC. TUNEL assay was performed to examine the apoptosis of hepatocytes. Proteins of p53, cleaved-caspase 9, cleaved-caspase 3, Bcl-2, and Bax as well as p38 were detected. Results showed that lycopene alleviated the liver pathological damage and reduced the injury to liver function induced by nano-TiO 2 , as well as decreased nano-TiO 2 -induced ROS. Meanwhile, lycopene mitigated apoptosis resulting from nano-TiO 2 , accompanied by the reversed expression of apoptosis-related proteins. Furthermore, lycopene significantly reversed the upregulation of p-p38 induced by nano-TiO 2 . In conclusion, this study demonstrated that nano-TiO 2 resulted in hepatocyte apoptosis through ROS/ROS-p38 MAPK pathway and led to liver function injury. Lycopene protected mice liver against the hepatotoxicity of nano-TiO 2 through antioxidant property.
研究领域:
毒理学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Current Research in Food Science
·
2026
·
IF 7.7
Kai Na,Cheng Chao,Tianfei Yu,Liqun Wang,Xiaotong Liu,Li Zhang,Kejue Feng,Junhua Lei,Yu Xiong,Xiaohua Guo
2′-Fucosyllactose (2′-FL), the most abundant human milk oligosaccharide (HMO), exhibits potent anti-inflammatory properties, yet the underlying mechanisms remain incompletely understood. This study employed an integrated approach combining in vitro fermentation systems, Caco-2 cell assays, in vivo murine colitis models, and molecular docking simulations to elucidate the dual mechanisms of 2′-FL action. In vitro fermentation revealed that 2′-FL selectively enhanced propionate and butyrate production while enriching Bacteroides acidifaciens and Allobaculum stercoricanis , key short-chain fatty acids (SCFAs)-producing taxa. In enterotoxigenic Escherichia coli (ETEC)-infected Caco-2 cells, 2′-FL suppressed TLR4/p38 MAPK signaling and inflammation, an effect mirrored by propionate and butyrate. Similarly, in the dextran sulfate sodium (DSS)-induced mouse colitis model, 2′-FL inhibited this signaling pathway, alleviated inflammation, and, in parallel, specifically elevated levels of propionate and butyrate. Molecular docking analyses also indicated that 2′-FL and its metabolites, propionate and butyrate, exhibit binding to the TLR4–MD2 complex with specific affinity. These results support a coordinated mechanism whereby 2′-FL alleviates intestinal inflammation through putative TLR4 antagonism and the microbiota-derived SCFAs, both of which converge to modulate the TLR4/p38 MAPK-dependent signaling axis. Our work provides a mechanistic foundation for 2′-FL as a precision prebiotic targeting gut inflammation via host-microbe crosstalk.
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2021
·
IF 6.025
Wanyue Huang,Menglin Liu,Bonan Xiao,Jian Zhang,Miao Song,Yanfei Li,Zheng Cao
Aflatoxin B 1 (AFB 1 ) is an unavoidable food and environmental contaminant, which can lead to disorders in spermatogenesis and its mechanism remains unclear. The blood-testis barrier (BTB) is responsible for ensuring normal spermatogenesis in testes. Therefore, we hypothesized that disruption of the BTB was involved in AFB 1 -induced spermatogenesis disorders. To confirm our hypothesis, male Kunming mice were orally gavaged AFB 1 (0, 0.375, 0.75, or 1.5 mg/kg) for 30 days. Primarily, we first proved that AFB 1 disrupted the BTB integrity. Then, AFB 1 decreased BTB-related junction protein expression and elevated Sertoli cell apoptosis , which were associated with oxidative stress . Additionally, AFB 1 upregulated the p-p38 MAPK/p38 MAPK ratio. These results collectively indicated that AFB 1 disrupted the BTB via reducing the expression of BTB-related junction protein and promoting apoptosis in mice testes, which were associated with the oxidative stress-mediated p38 MAPK signaling pathway.
研究领域:
毒理学
·
生殖生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PeerJ
·
2024
·
IF 2.3
Lingmin Zhang,Jianguo Zhang,Yingying Zhou,Qingqing Xia,Jing Xie,Bihong Zhu,Yang Wang,Zaixing Yang,Jie Li
Background Cadmium (Cd) is hazardous to human health because of its cytotoxicity and long biological half-life. Azoramide is a small molecular agent that targets the endoplasmic reticulum (ER) and moderates the unfolded protein response. However, its role in Cd-induced cytotoxicity remains unclear. This study was performed to investigate the protective effect of azoramide against Cd-induced cytotoxicity and elucidate its underlying mechanisms. Methods Inductively coupled plasma‒mass spectrometry was used to measure Cd concentrations in each tissue of ICR male mice. The human proximal tubule epithelial cell line HK-2 and the human retinal pigment epithelial cell line ARPE-19 were used in the in vitro study. Cell apoptosis was determined by DAPI staining, JC-1 staining, and annexin V/propidium iodide double staining. Intracellular oxidative stress was detected by MitoSOX red staining, western blot, and quantitative real-time PCR. Moreover, ER stress signaling, MAPK cascades, and autophagy signaling were analyzed by western blot. Results The present data showed that Cd accumulated in various organs of ICR mice, and the concentrations of Cd in the studied organs, from high to low, were as follows: liver > kidney > testis > lung > spleen > eye. Our study demonstrated that azoramide inhibited ER stress by promoting BiP expression and suppressing the PERK-eIF2α-CHOP pathway. Additionally, we also found that azoramide significantly decreased ER stress-associated radical oxidative species production, attenuated p38 MAPK and JNK signaling, and inhibited autophagy, thus suppressing apoptosis in HK-2 and ARPE-19 cells. Conclusion Our study investigated the effect of azoramide on Cd-induced cytotoxicity and revealed that azoramide may be a therapeutic drug for Cd poisoning.
研究领域:
毒理学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND FUNCTION
·
2013
·Vol. 32
·期 2
·125-132
·
IF 1.854
Jianbo Song,Lichao Liu,Lingrui Li,Jing Liu,Erqun Song,Yang Song
The protective roles of lipoic acid (LA)/vitamin C (VC) and mesna on preventing cyclophosphamide (CYP)-induced haemorrhagic cystitis (HC) were investigated. Swiss mice were divided into five groups randomly. HC was induced by a single dose of CYP injection (150-mg kg −1 bodyweight). Group I was injected with saline (four times in total) throughout as control group. Group II received CYP and three equal doses of saline. Group III received CYP and three doses of mesna, whereas Group IV (or Group V) received CYP, mesna + two doses of VC (or LA). All injections were performed intraperitoneally. After 24 h of cystitis induction, the bladders were collected for all the experiments. Histological characterization showed that CYP injection resulted in severe HC. Reactive oxygen species (ROS) and thiobarbituric acid reactive substances' levels were increased in CYP group. The activities of antioxidant enzymes, e.g. superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase, were inhibited significantly in CYP groups, respectively. In addition, activation of c-jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in the mechanism of CYP-induced HC but not extracellular signal regulated kinases (ERK). Significant suppression of p38 phosphorylation on Group V suggests that LA and mesna may have synergistic beneficial effect. In Groups III–V, all the parameters of HC and oxidative stress were inhibited significantly. Taking together, we found that these results illustrated that ROS play an important role on CYP-induced HC and the administration of LA/VC with mesna may have therapeutic potential against CYP-induced bladder HC. Copyright © 2013 John Wiley & Sons, Ltd.
研究领域:
药理学
·
毒理学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Shuanghui Lu,Xiu Chen,Yujia Chen,Yingqiong Zhang,Jun Luo,Huidi Jiang,Luo Fang,Hui Zhou
Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of renal tubular cells promotes renal fibrosis and the progression of chronic kidney disease (CKD). PDZ domain-containing 1 (PDZK1) is highly expressed in renal tubular epithelial cells; however, its role in TGF-β1-induced EMT remains poorly understood. The present study showed that PDZK1 expression was extremely downregulated in fibrotic mouse kidneys and its negative correlation with TGF-β1 expression and the degree of renal fibrosis. In addition, TGF-β1 downregulated the mRNA expression of PDZK1 in a time- and concentration-dependent manner in vitro . The downregulation of PDZK1 exacerbated TGF-β1-induced EMT upon oxidative stress, while the overexpression of PDZK1 had the converse effect. Subsequent investigations demonstrated that TGF-β1 downregulated PDZK1 expression via p38 MAPK or PI3K/AKT signaling in vitro , but independently of ERK/JNK MAPK signaling. Meanwhile, inhibition of the p38/JNK MAPK or PI3K/AKT signaling using chemical inhibitors restored the PDZK1 expression, mitigated renal fibrosis, and elevated renal levels of endogenous antioxidants carnitine and ergothioneine in adenine-induced CKD mice. These findings provide the first evidence suggesting a negative correlation between PDZK1 and renal fibrosis, and identifying PDZK1 as a novel suppressor of renal fibrosis in CKD through ameliorating oxidant stress.
研究领域:
肾病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Sensors
·
2020
·
IF 7.333
Dan Sun,Weiqing Xu,Chongyang Liang,Wei Shi,Shuping Xu
High-efficiency induction of bone marrow mesenchymal stem cells (BMSCs) to osteogenic differentiation in vitro can help solve a series of bone diseases such as bone injury, fracture repair, and osteoporosis. In order to explore the optimal conditions for different chemical inducers to promote BMSCs differentiation and the possible differentiation mechanisms, we developed a smart nanoprobe that can achieve in situ alkaline phosphatase (ALP) activity detection during osteogenic differentiation in cells. The smart nanoprobe (Au@BCIP) was designed as the surface decoration of gold nanoparticles (AuNPs) with 5-bromo-4-chloro-3-indolyl phosphate (BCIP). The nanoprobe was co-cultured with differentiated BMSCs at different stages to monitor ALP activity based on an ALP-catalyzed hydrolysis reaction with BCIP as a substrate. The product can be quickly oxidized by dissolved oxygen to obtain a Raman-active species (5,5′-dibromo-4,4′-dichloro-1H,1H-[2,2′] biindolylidene-3,3′-dione). The SERS sensitivity was greatly improved by resonating the excitation wavelength of 632.8 nm. It is a new strategy for tracing bone disease-related ALP activity in an in vivo model with high sensitivity and selectivity and non-invasion. By using this nanoprobe, osteogenic differentiation of cells under osteogenic supplements was assessed and the p38 MAPK signaling pathway for osteogenic differentiation was experimentally evidenced, which are of significance for understanding BMSCs and regulating their osteogenic differentiation process.
研究领域:
生物医学工程
·
细胞生物学
·
骨科医学
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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）