Scientific Reports
·
2023
·Vol. 13
·期 1
·1-13
·
IF 4.6
Li Shaocong,He Qi,Chen Baihao,Zeng Jiaxu,Dou Xiangyun,Pan Zhaofeng,Xiao Jiacong,Li Miao,Wang Fanchen,Chen Chuyi,Lin Yuewei,Wang Xintian,Wang Haibin,Chen Jianfa
Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2025
·
IF 5.1
Yanqiu Zhou,Junfang Shu,Yueying Zhao,Xiaorong Wu,Zhijun He,Xinzhe Lyu,Yong Zhou,Ling Ma
Background: Obesity is turning into a more critical problem for public health. Vitamin D3 (VD3) may be strongly linked to obesity.Objectives: The study aims to examine the influence of VD3 on IL-27 levels and the molecular mechanism by which VD3 affects white fat beige through the IL-27/P38MAPK/PGC-1α pathway.Methods: Firstly, a small sample population study was conducted to compare the disparities in serum 25(OH)D3 and IL-27 between individuals with obesity and healthy control groups. Secondly, twenty-four Wistar rats were separated into three groups: CON, HFD, and HFD + VD3 groups. Following 7 weeks of intervention, detection of biochemical indicators in serum by enzyme-linked immunosorbent assay (ELISA), mRNA, and protein expression of vitamin D receptor (VDR), IL-27R, P38MAPK, PGC-1α, and UCP-1 in inguinal adipose tissue by RT-qPCR and western blot. Finally, 3T3-L1 cells were induced into a hypertrophic adipose model, knock down IL-27 or PGC-1α using small interfering RNA, treated with 100 nM Calcitriol for 24 h, and divided into CON, PA, PA + 1,25(OH)2D3, PA + si IL-27, PA + si IL-27 + 1,25(OH)2D3, PA + si PGC-1α, and PA + si PGC-1α + 1,25(OH)2D3 groups. Detection of TC, TG, and IL-27 levels by ELISA, mRNA, and protein expression of VDR, IL-27R, P38MAPK, PGC-1α, UCP-1, and CD137 in cell supernatant by RT-qPCR and western blot.Results: A correlation was identified between serum 25(OH)D3 and IL-27 in the population-based study. However, no statistically significant difference in serum 25(OH)D3 or IL-27 levels was observed between the observation group and the control group. After VD3 intervention, TC, TG, and the number of LDs were significantly reduced in both HFD rats and 3T3-L1 cells, and serum IL-6 and MCP-1 in HFD rats were decreased. Meanwhile, there was a significant increase in mRNA and protein expression for VDR, IL-27R, P38MAPK, and PGC-1α. The expressions of the UCP-1 protein and the CD137 mRNA dramatically increased. Knockdown of IL-27 eliminated the increasing effect of calcitriol on the expression of P38MAPK, PGC-1α, UCP-1, and CD137 in 3T3-L1 cells, and knockdown of PGC-1α eliminated the increasing effect of calcitriol on the expression of UCP-1 and CD137 in 3T3-L1 cells.Conclusion: The study shows that VD3 may promote white fat beige through the IL-27/P38MAPK/PGC-1α pathway.
研究领域:
内分泌学
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分子生物学
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肥胖研究
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代谢紊乱
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2023
·Vol. 46
·期 1
·26-34
·
IF 2
Chen Huang,Tao Zhou,Lihua Ma,Shipeng Zhao
Oxaliplatin (OXA) is a usual chemotherapeutic agent applied in the colorectal cancer (CRC) clinical treatment. Interferon-alpha inducible protein 6 (IFI6) has been proved to promote proliferation and suppress apoptosis in several tumor cells, while the impacts of IFI6 on OXA resistance in CRC still need exploration. HCT116 and SW620 cells were used as the parental to obtain OXA-resistant cells. The influence of IFI6 on OXA sensitivity, cell proliferation and apoptosis were evaluated by overexpression or knockdown IFI6 in cells. In this work, we found that the level of IFI6 was significantly enhanced in HCT116/OXA and SW620/OXA cells as compared to the parental cells. Overexpression of IFI6 decreased the sensitivity of HCT116 and SW620 cells to OXA. However, knockdown of IFI6 enhanced the sensitivity of HCT116/OXA and SW620/OXA cells to OXA. And upregulated IFI6 promoted the proliferation and repressed apoptosis in HCT116 cells, while suppressed IFI6 markedly reduced proliferation and increased apoptosis in HCT116/OXA cells. Additionally, IFI6 suppressed the phosphorylation level of p38, and silenced IFI6 enhanced it. The addition of the p38 kinase inhibitor, SB203580, alleviated the decreased cell proliferation and increased apoptosis in HCT116/OXA cells. Suppressed IFI6 enhanced the reactive oxygen species (ROS) level in HCT116/OXA cells, and blockade of ROS with N-acetyl-L-cysteine (NAC) decreased the enhancement level of ROS and the phosphorylation level of the p38, which was induced by IFI6 down-regulation. We, therefore, implied that suppressed IFI6 reverses OXA-resistance of CRC cells via promoting the ROS-induced p38 mitogen-activated protein kinase (MAPK) signaling pathway.
研究领域:
肿瘤学
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分子生物学
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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
TOXICOLOGY IN VITRO
·
2023
·
IF 3.2
Huan Hou,Yaping Yang,Rong Chen,Zhiping Guo
Trastuzumab (TRZ) is a novel targeted anti-tumor agent that significantly improve the survival of patients with human epidermal growth factor receptor (HER2) positive breast cancer. However, its clinical application is limited due to the side effects of cardiotoxicity. Osthole (OST), a coumarin derivative isolated from Cnidium monnieri (L.) Cusson, has previously demonstrated cardioprotective effects. The aim of this study was to observe the protective effect of OST on TRZ-induced cardiomyocytes damage and to explore its potential mechanism. The results showed that OST pretreatment could significantly inhibit TRZ-induced cardiomyocytes damage, markedly increase the ratio of LC3II/I and Beclin-1 protein expression, and reduce the protein expression of p62. OST pretreatment significantly attenuated oxidative stress and apoptosis induced by TRZ, as evidenced by reducing intracellular ROS level, the Bax/Bcl-2 ratio, and Caspase-3 protein expression. Additionally, OST markedly increased the phosphorylation level of p38MAPK and decreased the mTOR phosphorylation level. However, the effects of OST on enhancing autophagy, reducing oxidative stress, apoptosis, and the phosphorylation level of mTOR were reversed after the addition of 3-MA or SB203580. Molecular docking results indicated that OST exerted a good binding ability with the p38MAPK protein. Our findings suggested that OST could protect TRZ-induced cardiomyocytes damage by enhancing autophagy via the p38MAPK/mTOR signaling pathway.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Di Zhang,Bei Jing,Zhenni Chen,Xin Li,Huimei Shi,Yachun Zheng,Shiquan Chang,Guoping Zhao
Background Nonsteroidal anti-inflammatory drugs are used to relieve sciatica, but their effects are not satisfactory. Purpose This study aimed to explore the therapeutic effects of ferulic acid on sciatica. Methods Thirty-two SD rats were randomly divided into 4 groups, i.e., sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and ferulic acid group. We conducted behavioural tests, ELISA, PCR, Western blots, and immunofluorescence analysis. Specific inhibitors were used in cell experiments to explore the related mechanisms. Results Thermal hyperalgesia was induced after CCI operation, and ferulic acid relieved thermal hyperalgesia. In addition, ferulic acid decreased the IL1β, IL6, TNF-α, and CRP mRNA levels; the IBA-1, iNOS, IL1β, RhoA, RhoA-GTP, COX2, Rock1, TRPV1, TRPA1, and p-p38MAPK levels in dorsal root ganglion (DRG) neurons; and the LPS, CRP, substance P (SP), and prostaglandin E2 (PGE2) levels in serum, and these levels were higher in the CCI group. In the cell experiments, LPS induced M1 polarization of GMI-R1 cells via the RhoA/Rock pathway. Ferulic acid attenuated LPS-induced M1 polarization by decreasing the levels of M1 polarization markers, including IL1β, IL6, TNF-α, iNOS, and CD32, and increased M2 polarization by increasing the levels of M2 polarization markers, including CD206 and Arg-1. LPS treatment clearly increased the iNOS, IL1β, RhoA, Rock1, Rock2 and p-p38 MAPK levels and reduced Arg-1 expression, and ferulic acid reversed these changes. Conclusion Ferulic acid can inhibit peripheral sensitization by reducing the levels of inflammatory factors, TRPA1 and TRPV1 through the RhoA/p38 MAPK pathway to alleviate sciatica.
研究领域:
药理学
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神经科学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Oncology
·
2022
·
IF 4.501
Hongliang You,Dao Wang,Linlin Wei,Jiao Chen,Huanhuan Li,Yufeng Liu
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, with a feature of easy to induce multidrug resistance and relapse. Abundant studies have proved that iron overload strengthens the growth and metastasis of tumor cells. Herein, we found that deferoxamine (DFO) effectively decreased the concentration of intracellular iron in ALL cells. DFO inhibited proliferation, induced apoptosis, and obstructed cell cycle of ALL cells, whereas DFO and dextriferron (Dex) used in combination significantly decreased the sensitivity of ALL cells to DFO. Reactive oxygen species (ROS) level was reduced in ALL cells treated with DFO, and the combination of DFO and Dex reversed the effects of DFO. In vivo, DFO inhibited mouse tumor growth. Besides, cyclinD1, β-catenin, c-Myc, hypoxia inducible factor 1 (HIF-1), p-p38MAPK, and p-ERK1/2 protein levels were significantly downregulated, and the levels of prolyl hydroxylase-2 (PHD-2) were upregulated after treated with DFO, whereas Dex treatment reversed those in vivo and in vitro. In conclusion, DFO inhibited the proliferation and ALL xenograft tumor growth, obstructed the cell cycle, and induced apoptosis of ALL cells, probably via inactivating the ROS/HIF-1α, Wnt/β-catenin, and p38MAPK/ERK signaling.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Ke Du,Yuting Liu,Lu Zhang,Lixia Peng,Wenjing Dong,Yajie Jiang,Mingming Niu,Yuanchao Sun,Chuanhong Wu,Yujuan Niu,Yonghe Ding
Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.
研究领域:
肿瘤学
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心脏病学
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发育生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Xiaochen Li,Yang Ju,Xinxin Yang,Tianjiao Li,Shuai Wang,Yongrui Bao,Xiansheng Meng
Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with pro-tumor inflammation playing a critical role in its initiation and progression. Chronic inflammation acts as a major driving force and a distinct mechanism underlying tumorigenesis. Although previous studies have demonstrated the importance of the VEGF/p38MAPK and p38MAPK/HSP27 signaling pathways in CRC-associated inflammation, a comprehensive understanding of the entire pro-tumor inflammatory mechanism remains incomplete.Methods: This study combined network pharmacology analysis and in vivo pharmacodynamic experiments using a p38MAPK pathway inhibitor to systematically identify and validate the VEGF/p38MAPK/HSP27 pro-tumor inflammatory signaling pathway. Western blotting was used to confirm key target proteins. Molecular docking and microscale thermophoresis (MST) experiments were conducted to screen active compounds from Patrinia villosa (PV). Molecular dynamics (MD) simulations evaluated the stability and drug-likeness of compound-target interactions.Results: Key proteins VEGF, p38MAPK, and HSP27 were identified as critical components of the signaling pathway. Three active compounds rutin, nicotiflorin, and 4,5-dicaffeoylquinic acid (4,5-Dicqa) were found to bind these targets with high affinity. MD simulations supported the stability of these interactions and their potential as drug candidates.Conclusion: This study provides theoretical and experimental evidence for pharmacological targets involved in pro-tumor inflammation in CRC. The findings offer valuable insights for developing novel anti-inflammatory therapeutics targeting the VEGF/p38MAPK/HSP27 signaling pathway.
研究领域:
肿瘤学
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药理学
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生物信息学
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分子生物学
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民族药理学
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2024
·Vol. 50
·期 1
·1-16
·
IF 3.7
Lao Dayuan,Gong Zhuowei,Li Taiyan,Mo Xuean,Huang Wen
The clinical manifestations of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may be closely related to the integrity of the blood–brain barrier (BBB). The P38 mitogen-activated protein kinase (P38MAPK) pathway plays a protective role in neurodegenerative diseases. However, whether the P38MAPK pathway is involved in the underlying mechanism of tight junction (TJ) protein disruption and neuronal damage has not been elucidated. Therefore, in this study, a mouse model of anti-NMDAR encephalitis was established by active immunization with NMDAR NR1 356-385 peptides. The critical pathways of P38MAPK were screened by interaction network and co-enrichment analysis. The role of P38MAPK pathways was investigated by the injection of P38MAPK inhibitor SB203580 (10 mg/kg, i.p.). Compared with the control group, the expression of occludin and zonula occludens (ZO)-1 in NMDAR NR1 356-385 group mice was downregulated, and the structure and function of BBB were damaged. However, after the intervention of SB203580, the activation of the P38MAPK was inhibited, the expression of matrix metalloproteinase 9 (MMP9) was reduced, and the function of BBB was improved. Meanwhile, inhibiting the P38MAPK pathway reversed the degradation of NMDAR NR1, while reducing the expression of the glial fibrillary acidic protein (GFAP) and pro-inflammatory factor tumor necrosis factor (TNF-α). It also relieved the damage of neuron-specific nucleus (NeuN), thus alleviating psychobehavioral symptoms. In conclusion, our results suggested that the P38MAPK pathway is involved in BBB destruction and neurobehavioral change in mice with anti-NMDAR encephalitis. Targeting the P38MAPK pathway may be a promising option for the treatment of anti-NMDAR encephalitis.
研究领域:
神经科学
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免疫学
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药理学
✓ 已验证
DOI
高影响因子
CNS Neuroscience & Therapeutics
·
2023
·
IF 5.5
Xin Li,Huimei Shi,Di Zhang,Bei Jing,Zhenni Chen,Yachun Zheng,Shiquan Chang,Li Gao,Guoping Zhao
Background This study aimed to investigate the potential mechanism of paeonol in the treatment of neuropathic pain. Methods Relevant mechanisms were explored through microglial pseudotime analysis and the use of specific inhibitors in cell experiments. In animal experiments, 32 SD rats were randomly divided into the sham operation group, the chronic constrictive injury (CCI) group, the ibuprofen group, and the paeonol group. We performed behavioral testing, ELISA, PCR, Western blotting, immunohistochemistry, and immunofluorescence analysis. Results The pseudotime analysis of microglia found that RhoA, Rock1, and p38MAPK were highly expressed in activated microglia, and the expression patterns of these genes were consistent with the expression trends of the M1 markers CD32 and CD86. Paeonol decreased the levels of M1 markers (IL1β, iNOS, CD32, IL6) and increased the levels of M2 markers (IL10, CD206, ARG-1) in LPS-induced microglia. The expression of iNOS, IL1β, RhoA, and Rock1 was significantly increased in LPS-treated microglia, while paeonol decreased the expression of these proteins. Thermal hyperalgesia occurred after CCI surgery, and paeonol provided relief. In addition, paeonol decreased the levels of IL1β and IL8 and increased the levels of IL4 and TGF-β in the serum of CCI rats. Paeonol decreased expression levels of M1 markers and increased expression levels of M2 markers in the spinal cord. Paeonol decreased IBA-1, IL1β, RhoA, RhoA-GTP, COX2, Rock1, and p-p38MAPK levels in the spinal dorsal horn. Conclusion Paeonol relieves neuropathic pain by modulating microglial M1 and M2 phenotypes through the RhoA/p38 MAPK pathway.
研究领域:
药理学
·
神经科学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL TRANSPLANTATION
·
2022
·
IF 4.139
Yangming-Fan,Jianjun-Ge
Coronary artery bypass grafting remains the gold standard in the therapy of advanced-stage patients. But the vein grafts are prone to restenosis or failure. Pentoxifylline (PTX) is a methylxanthine derivative with a function of inhibiting cell proliferation. We thus applied PTX locally to the vein grafts to study its effect on the inhibition of graft restenosis using a rat vein graft model. Morphometric results showed a significant decrease in the thickness of vein grafts intimal and medial at day 28 after the bypass operation. Results from Western blot and immunohistochemistry showed that PTX also significantly reduced the proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (α-SMA) expression, and phosphorylation of p38 in vein grafts. These results firstly discovered the positive role of PTX in preventing the vein grafts restenosis and the mechanism may be inhibition of vascular smooth muscle cells (VSMCs) proliferation via the p38MAPK pathway.
研究领域:
心血管疾病
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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
Molecular Medicine Reports
·
2023
·Vol. 27
·期 2
·1-11
·
IF 3.4
Jing Zhao,Mingming Ma,Lei Li,Gaoli Fang
Oxysophoridine (OSR) is an alkaloid extracted from Sophora alopecuroides L. and exerts beneficial effects in cerebral ischemia/reperfusion (I/R) injury. However, the molecular mechanism underlying the regulatory effects of OSR in cerebral I/R injury remains unclear. In the present study, a cerebral I/R injury rat model was established by occlusion of the right middle cerebral artery. Hematoxylin and eosin and triphenyltetrazolium chloride staining were performed to assess histopathological changes and the extent of cerebral injury to the brain. A Cell Counting Kit‑8 and TUNEL assay and western blotting were performed to assess cell viability and apoptosis. Ferroptosis and oxidative stress were evaluated based on ATP and Fe2+ levels and DCFH‑DA staining. The protein expression levels of inflammatory factors were assessed using ELISA. The protein expression levels of members of the toll‑like receptor (TLR)4/p38MAPK signaling pathway were evaluated using immunofluorescence staining and western blotting. The results demonstrated that OSR decreased brain injury and neuronal apoptosis in the hippocampus in I/R‑induced rats. OSR inhibited reactive oxygen species (ROS) production, decreased levels of ATP, Fe2+ and acyl‑CoA synthetase long‑chain family member 4 (ACSL4) and transferrin 1 protein and increased the protein expression levels of ferritin 1 and glutathione peroxidase 4. Furthermore, OSR blocked TLR4/p38MAPK signaling in brain tissue in the I/R‑induced rat. In vitro experiments demonstrated that TLR4 overexpression induced generation of ROS, ATP and Fe2+, which promoted the expression of ferroptosis‑associated proteins in hippocampal HT22 neuronal cells. The ferroptosis inducer erastin decreased the effects of OSR on oxygen‑glucose deprivation/reoxygenation (OGD/R)‑induced cell viability, oxidative stress and inflammatory response. Together, the results demonstrated that OSR alleviated cerebral I/R injury via inhibition of TLR4/p38MAPK‑mediated ferroptosis.
研究领域:
神经科学
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药理学
·
细胞生物学
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分子生物学
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病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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