JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2025
·Vol. 29
·期 6
·e70470
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IF 4.2
Chuchu Xu,Renjun Zhu,Qingfeng Dai,Yaoqing Li,Gengyuan Hu,Kelong Tao,Yuhong Xu,Guangen Xu,Guolin Zhang
The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC 50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK–STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC.
研究领域:
肿瘤学
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分子生物学
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药物研发
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Hui-Ying Xu,Meng-Ting Jiang,Yu-Feng Yang,Yisha Huang,Wei-Dong Yang,Hong-Ye Li,Xiang Wang
Fucoxanthin, an abundant carotenoid in marine algae, has garnered attention for its diverse health benefits, including anti-inflammatory and anticancer properties. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and damage. This study investigated the therapeutic potential of fucoxanthin extracted from Phaeodactylum tricornutum in collagen-induced RA. Our results demonstrated that fucoxanthin significantly alleviated RA symptoms, including weight loss, joint swelling, and decreased appetite. Histological analysis revealed that fucoxanthin mitigated synovial inflammation, cartilage damage, and bone erosion. Mechanistically, transcriptomic analysis and cell experiments indicated that fucoxanthin suppressed the JAK-STAT signaling pathway by downregulating the expression of inflammatory cytokines, such as IL-6 and IL-1β. Furthermore, metagenomic analysis suggested that fucoxanthin restored the altered gut microbiota composition associated with RA. These findings highlight the therapeutic potential of fucoxanthin from P. tricornutum in the management of RA by targeting multiple pathways, including inflammation and gut microbiota.
研究领域:
药理学
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免疫学
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微生物学
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DOI
PubMed
高影响因子
International Journal of Environmental Research and Public Health
·
2016
·Vol. 13
·期 11
·1085
·
IF 2.035
Yiyang Jia,Te Liu,Liting Zhou,Jian Zhu,Juan Wu,Di Sun,Jin Xu,Qi Wang,Huaiji Chen,Feng Xu,Yuezhu Zhang,Tianrong Zhang,Hongbo Liu,Lin Ye
The most widely used plasticizer, di-(2-ethylhexyl) phthalate (DEHP), is known to affect lipid metabolism and adipogenesis. We studied the effects of dietary DEHP exposure on metabolism in rats as well as the role of the JAK/STAT pathway in this process. Eighty rats were exposed to DEHP (0, 5, 50 and 500 mg/kg/d) through dietary intake for 4 weeks. We then collected blood samples, liver, and adipose tissues to detect modifications in the levels of serum lipids, leptin, adiponectin and insulin. JAK3, STAT5a and PPARγ expression were detected at both the gene and protein levels. The activation of JAK3 and STAT5a was also detected. The DEHP-exposed rats had increased body weight, serum lipid, insulin, and leptin levels. Moreover, the JAK3/STAT5a pathway was activated in the adipose tissue; however, this pathway was not activated in the liver. The mRNA of SREBP-1c in the liver was increased significantly among each of the groups, in contrast to the levels found in the mature SREBP-1c protein form. Furthermore, the expression ofFABP4,AcoxandFASnwas decreased in the liver, but increased in adipose tissue. Thus, we conclude that exposure to DEHP reduces the hydrolysis of lipid and promotes triglyceride accumulation by oppositely regulating the activation state of JAK/STAT pathway in the liver and adipose tissue, resulting in the disorder of body lipid metabolism and obesity.Keywords:di-(2-ethylhexyl) phthalate;JAK/STAT;lipid metabolism;adipose tissue
研究领域:
毒理学
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代谢研究
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分子生物学
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PubMed
高影响因子
Antioxidants
·
2022
·Vol. 11
·期 12
·2360
·
IF 7.675
Jian Jin,Yiyi Shan,Liangliang Zhang,Zhengchang Wu,Shenglong Wu,Mingan Sun,Wenbin Bao
Fumonisin B1 (FB1) is a mycotoxin that poses a great threat to agricultural production and the health of humans and animals. Pterostilbene (PTE) is a natural plant polyphenolic compound with good anti-inflammatory, antioxidant and cell regeneration effects, yet its effectiveness in treating FB1-induced cytotoxicity remains to be explored. In this study, we used porcine alveolar macrophages (3D4/21) as a model to characterize the cytotoxicity induced by FB1, and to investigate the potential alleviating effect of PTE on FB1-induced cytotoxicity. We demonstrate that FB1 induces cytotoxicity, apoptosis, pro-inflammatory cytokine production and mitochondrial damage, which can be largely recovered by PTE treatment, suggesting the promising application of PTE to treat FB1-induced damage. Mechanistically, FB1 activates the JAK/STAT signaling pathway, while PTE attenuates FB1-induced cytotoxicity through the inhibition of key JAK/STAT genes such asJAK2andSTAT3. Overall, our study characterized the molecular mechanism for FB1-induced cytotoxicity and found PTE to be a promising component which can alleviate FB1-induced cytotoxicity by interfering in the activation of JAK/STAT pathway.Keywords:fumonisin B1;pterostilbene;alveolar macrophage;cytotoxicity;JAK/STAT signaling pathway;pig
研究领域:
毒理学
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药理学
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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 APPLIED TOXICOLOGY
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2025
·
IF 2.8
Yaqi Li,Zhanbing Sun,Yuqi Tong,Chenxi Yan,Lian Huang,Zhaohui Zhang
Beryllium and its compounds are classified as carcinogens, and prolonged exposure can trigger chronic beryllium disease. The Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling is known to play a critical role in the development and progression of numerous diseases. Leukemia inhibitory factor (LIF), a key upstream cytokine of the JAK-STAT pathway, has been implicated in regulating inflammatory responses and epithelial-mesenchymal transition (EMT) in various diseases. However, the specific involvement of the JAK-STAT pathway and LIF in beryllium sulfate (BeSO₄)–induced EMT in human bronchial epithelial (16HBE) cells remains unclear. To investigate the regulatory mechanisms, we examined the effects of BeSO₄ on 16HBE cells and targeted the JAK-STAT pathway using both pharmacological inhibition (niclosamide) and genetic silencing of LIF. Subsequently, we assessed cell morphology, proliferative capacity, inflammatory protein levels, and EMT marker expression. Our findings demonstrated that BeSO₄ exposure inhibited 16HBE cell proliferation and activated the JAK-STAT pathway. Pretreatment with niclosamide significantly mitigated cellular inflammation and the EMT process induced by BeSO₄. Additionally, silencing LIF markedly reduced JAK-STAT pathway activation and decreased the expression of EMT markers. This study uncovers a novel mechanism underlying BeSO₄-induced EMT in 16HBE cells, providing valuable insights into the molecular mechanisms of toxicity induced by beryllium and its compounds.
研究领域:
毒理学
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细胞生物学
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呼吸系统疾病
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Wenjing Pu,Xuesheng Chu,Shiwen Xu,Xueyan Dai,Li Xiao,Ting Cui,Bingyan Huang,Guoliang Hu,Caiying Zhang
Molybdenum (Mo) is an essential nutrient in living organisms. Although numerous researchers have noticed the health damage caused by excessive Mo, the underlying mechanism of excessive Mo-induced nephrotoxicity remains poorly understood. A gene crosstalk called competitive endogenous RNAs (ceRNAs) can interpret many regulatory mechanisms molecularly. But there are few researches have tried to explain the damage mechanism of excess Mo to organisms through ceRNAs network. To clarify this, the study explored the changes in lncRNAs and miRNAs expression profiles in the kidney of ducks exposed to excess Mo for 16 weeks. The sequencing results showed that Mo exposure caused differential expression of 144 lncRNAs and 14 miRNAs. The occurrence of inflammation through the JAK/STAT axis was observed and the lncRNA-00072124/miR-308/OSMR axis was verified by a double luciferase reporter assay. Overexpression of miR-308 and RNA interference of OSMR reduced Mo-induced inflammatory factors, while miR-308 knockdown showed the opposite effect. Simultaneously, lncRNA-00072124 affected OSMR function as a ceRNA. Taken together, these results concluded that Mo exposure activated the JAK/STAT axis and induced inflammation mediated by the lncRNA-00072124/miR-308/OSMR crosstalk. The results might provide new views for revealing the toxic effects of excess Mo in duck kidneys.
研究领域:
毒理学
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分子生物学
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动物科学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Yi Wu,Yilin Ling,Yuqi Yang,Haoxing Long,Linghao Kong,Peiyang Song,Yujie Lu,Wanqiu Zhao,Wei Wang,Jingrong Zhu,Nan Wang
Obesity is a growing global health concern associated with severe metabolic disorders, necessitating the development of safer and more effective therapeutic strategies. Soybean sprout peptides (SSPs), derived from germinated soybeans, are bioactive compounds with potential antiobesity effects. This study aimed to investigate the molecular mechanisms of SSPs through an integrated approach combining network pharmacology, molecular docking, and in vivo experiments. SSP sequences were identified using UPLC-Orbitrap-MS/MS, and their bioactivity was predicted using PeptideRanker. Network pharmacology identified key SSP targets, including AKT1, SRC, STAT3, ESR1, FOS, and NFKB1, which are implicated in the PI3K-Akt and JAK-STAT pathways. Molecular docking validated strong interactions between SSPs and these targets. In vivo, SSP administration significantly reduced body weight gain, abdominal fat accumulation, and serum lipid abnormalities in high-fat-diet-induced obese mice while modulating gut microbiota composition by restoring the Firmicutes-to-Bacteroidetes ratio and reducing pathogenic taxa. Fecal metabolomics revealed that SSP alleviated oxidative stress and improved amino acid metabolism, contributing to its antiobesity effects. These findings suggest that SSP holds promise as a functional food ingredient or nutraceutical for obesity prevention and management.
研究领域:
营养学
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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
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Lei Zhao,Siyuan Han,Chengzhi Chai
Ethnopharmacological relevance Huangkui capsule (HKC), a Chinese patent medicine, has been widely used in China as adjuvant therapy for chronic kidney disease (CKD). It displays superior anti-proteinuria efficacy than losartan in patients with CKD at stages 1–2, however, the mechanism of HKC alleviating proteinuria has not been well elucidated. Aim of the study This study aims to confirm the therapeutic effect and investigate associated underlying mechanism of HKC against proteinuria by in vivo and in vitro experiments. Materials and methods We established a doxorubicin (DOX) induced proteinuria mouse model to evaluate kidney function by biochemical markers measurement and to observe histopathological alterations by hematoxylin and eosin (H&E), Masson's trichrome and Periodic Acid-Schiff (PAS)-stained sections of renal, respectively. Moreover, the expressions of Nephrin and Podocin were measured by immunohistochemistry (IHC) and western blotting analysis to investigate podocyte damage. Furthermore, we established Mouse Podocyte Clone-5 (MPC-5) injury model to identify the active components of HKC against podocyte damage by detecting the expressions of Nephrin, Podocin, and ZO-1 proteins. At last, the key protein levels of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were assessed by western blotting analysis to explore the underlying mechanism of HKC against proteinuria. Results Our results showed that HKC administration for three consecutive weeks dose-dependently ameliorated both renal function and histopathological damages, elevated the expressions of Nephrin and Podocin, the pivotal molecules maintaining filtration function of the podocyte, indicating the promising protective effect against podocyte injury under DOX exposure. Consistently, in vitro experiments showed HKC administration effectively reversed the abnormal expressions of Nephrin and Podocin in MPC-5 cells treated with DOX, suggesting its protective effect against podocyte injury to maintain filtration barrier integrity. In addition, Hibifolin was identified as the most active ingredients in HKC, which suppressed upstream JAK2/STAT3 and PI3K/Akt pathway phosphorylation to maintain the structural and functional integrity of podocyte filtration barrier. Of note, AG490 , a selective JAK2 inhibitor , was used to further affirm the role of Hibifolin involving in regulation JAK2/STAT3. Conclusions Our study suggested that HKC may protect podocytes via JAK2/STAT3 and PI3K/Akt pathway to display its effects of ameliorating proteinuria.
研究领域:
药理学
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肾病学
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民族药理学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Zhirui Du,Xueqiao Yan,Lin Cheng,Haiyu Shen,Guoguo Zhi,Baojie Li,Qian Yu
Background Dry eye disease (DED) is a multifactorial ocular condition marked by tear film instability, inflammation, and oxidative stress. Current therapies, including artificial tears and immunosuppressants, offer limited long-term benefit and potential side effects. Natural flavonoids such as luteolin possess anti-inflammatory and antioxidant properties, yet their therapeutic potential in DED remains underexplored. Purpose This study aimed to evaluate the therapeutic efficacy and mechanisms of luteolin in experimental DED. Methods Flavonoids were initially screened using lipopolysaccharide-stimulated RAW264.7 macrophages. A benzalkonium chloride-induced DED mouse model was treated with topical luteolin or cyclosporine A. Ocular surface evaluations included tear secretion, corneal fluorescein staining, and goblet cell density. Inflammatory and oxidative markers were examined via histology, immunofluorescence, and qPCR. RNA sequencing and network pharmacology were used to identify target pathways. In vitro studies with RAW264.7 cells and hyperosmolarity-stressed human corneal epithelial cells further validated mechanism-specific effects. Target engagement was further validated using pathway-specific pharmacological inhibitors. Ocular safety and pharmacokinetics were also assessed. Results Luteolin showed superior anti-inflammatory activity among tested flavonoids. It improved tear production, reduced epithelial damage, and preserved goblet cells. Mechanistically, it modulated macrophage-driven inflammation through JAK-STAT signaling and mitigated oxidative epithelial damage by suppressing the MAPK pathway. Transcriptomic and pharmacological analyses confirmed its dual immunomodulatory and cytoprotective roles. Combined STAT1/3 and MAPK inhibition mimicked its therapeutic effects. Topical luteolin was well-tolerated and achieved corneal bioavailability. Conclusions Luteolin provides a dual protective effect in DED by targeting inflammation and oxidative stress, supporting its development as a safe and effective disease-modifying therapy.
研究领域:
眼科
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免疫学
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分子生物学
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药理学
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炎症性疾病
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氧化应激
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信号转导
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转化医学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2018
·Vol. 17
·期 6
·8385-8390
·
IF 1.922
Ting Li,Qingwen Zeng,Xingming Chen,Guojiang Wang,Haiqing Zhang,Aihua Yu,Hairui Wang,Yang Hu
Acne rosacea is a type of chronic dermatosis with the characteristics of erubescence, angiotelectasis and pustule formation. However, current treatment methods are limited due to the side effects. Artesunate demonstrated a promising therapeutic efficacy with a high safety margin. HaCaT cells were treated with antibacterial peptide LL‑37 to simulate rosacea caused by Demodex folliculorum (D. folliculorum) infection. Cell Counting kit 8 and flow cytometry assays were performed to measure cellular proliferation, apoptosis, the stage of the cell cycle and reactive oxygen species generation in order to determine the level of cell damage. Then the damaged cells were treated with different concentrations of artesunate and doxycycline to determine the therapeutic effect of artesunate. Pro‑inflammatory cytokines tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6, IL‑8 and C‑C motif chemokine 2 (MCP‑1) were measured using an ELISA, while western blotting was used to detect the expression of Janus kinase 2 (JAK2) and signal transducer and transcription activator (STAT3). As a result, LL‑37 treated HaCaT cells decreased in cell viability, had an increased apoptotic rate and cell cycle arrest, indicating that cell damage caused by rosacea was simulated. In addition, upregulated concentrations of the pro‑inflammatory cytokines TNF‑α, IL‑6, IL‑8 and MCP‑1 were attenuated in the artesunate group in a dose‑dependent fashion, indicating the therapeutic effect of artesunate. Furthermore, higher concentrations of artesunate exhibited an improved effect compared with the doxycycline group. In addition, increased expression levels of JAK2 and STAT3 following treatment with LL‑37 suggested that rosacea caused by D. folliculorum infection may lead to inflammation through the JAK/STAT signaling pathway. In conclusion, the potential mechanism by which damage occurs in rosacea was revealed and a promising therapeutic method against rosacea was demonstrated.
研究领域:
皮肤科
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药理学
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细胞生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Li Jin,Xinyu Zheng,Chenxi Yu,Ping Li,Guiran Xiao
Metastasis is one of the most important factors related to malignant tumor development and therapeutic failure. Phytic acid (PA), a poly-phosphorylated inositol derivative in plant seeds and grains, has been shown to have antitumoral activity. However, the effect of PA on tumor metastasis and the underlying mechanisms remain uncharacterized. In the current study, we aimed to identify the effect of PA on tumor metastasis by employing a Drosophila model of malignant tumor Raf GOF Scrib −/− . We observed that PA supplementation in food inhibited the invasion and migration of tumors. Further studies indicated that PA drives Yki phosphorylation and inactivation through Lats kinase, which subsequently results in decreased expression of the JAK/STAT pathway ligands unpaired cytokines (Upds). Moreover, the reduced JAK/STAT pathway inhibits the recruitment and proliferation of hemocytes. To summarize, these findings provide valuable pathological and mechanistic insights into the potential application of PA for functional food or natural medicine development.
研究领域:
肿瘤学
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分子生物学
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遗传学
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产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
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IF 3.17
Pian Gong,Zhan Zhang,Yichun Zou,Qi Tian,Shoumeng Han,Zhou Xu,Jianming Liao,Ling Gao,Qianxue Chen,Mingchang Li
Tetramethylpyrazine (TMP) has been studied in depth and is widely used in the treatment of many kinds of diseases in China. However, whether it has neuroprotective effects on cerebral ischemia remains unclear. An ischemia/reperfusion (I/R) injury animal model was established via middle cerebral artery occlusion in this study. We set several different groups in which the rats were performed in different ways to explore the effects of TMP on blood-brainbarrier (BBB) disruption and determine whether TMP relieved BBB disruption through blocking the JAK/STAT signaling pathway. Our results showed that TMP could reduce the neurological functional loss, decrease the brain edema and BBB permeability, as well as increase the expression of tight junction proteins via inhibiting the activation of JAK/STAT signaling pathway. Overall, we demonstrated that TMP promoted neurological recovery after I/R injury via restoring the integrity and function of BBB.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）