TOXICOLOGY LETTERS
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2025
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IF 2.9
Chenyu Xiao,Qianru Li,Meiqi Li,Yongshu Han,Hubin Xu,Haimin Jiang,Suer Zhang,Zhen Jin,Leilei Gao
Iodoacetamide (IAcAm) is a harmful disinfection by-product. Studies have demonstrated that IAcAm can produce toxic effects in various tissues; however, its effect on female reproductive function remains unclear. To explore the effects of IAcAm on ovaries, we constructed a female mouse IAcAm toxicity model of free drinking model. The findings indicated that IAcAm exposure for five weeks did not affect the body growth of mice but increased the ovary/body weight ratio. At the tissue level, the numbers of atretic follicles increased. After the exposure, ovarian and blood samples were collected for analysis. IAcAm exposure caused changes in serum sex hormone levels, with an increase in follicle-stimulating hormone concentration(follicle-stimulating hormone) and a decrease in anti-Müllerian hormone concentration (anti-Müllerian hormone). Subsequent investigations revealed that IAcAm activated the transforming growth factor-β (TGF-β) signaling pathway and promoted ovarian fibrosis in mice. Simultaneously, IAcAm stimulated the granulosa cell apoptosis pathway and promoted granulosa cell apoptosis. Moreover, IAcAm interfered with mitochondrial function and increased reactive oxygen species, leading to a decrease in oocyte developmental potential. In conclusion, IAcAm exposure causes ovarian inflammation and leads to mitochondrial dysfunction in oocytes, affecting follicle maturation and reducing oocyte quality.
研究领域:
生殖生物学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Cardiovascular Medicine
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2021
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IF 6.05
Xu Yan,Qu Xiaobo,Zhou Jia,Lv Guangfu,Han Dong,Liu Jinlong,Liu Yuexin,Chen Ying,Qu Peng,Huang Xiaowei
Adriamycin (ADR)-based combination chemotherapy is the standard treatment for some patients with tumors in clinical, however, long-term application can cause dose-dependent cardiotoxicity. Pilose Antler, as a traditional Chinese medicine, first appeared in the Han Dynasty and has been used to treat heart disease for nearly a thousand years. Previous data revealed pilose antler polypeptide (PAP, 3.2KD) was one of its main active components with multiple biological activities for cardiomyopathy. PAP-3.2KD exerts protective effects againt myocardial fibrosis. The present study demonstrated the protective mechanism of PAP-3.2KD against Adriamycin (ADR)-induced myocardial injury through using animal model with ADR-induced myocardial injury. PAP-3.2KD markedly improved the weight increase and decreased the HW/BW index, heart rate, and ST height in ADR-induced groups. Additionally, PAP-3.2KD reversed histopathological changes (such as disordered muscle bundles, myocardial fibrosis and diffuse myocardial cellular edema) and scores of the heart tissue, ameliorated the myocardial fibrosis and collagen volume fraction through pathological examination, significantly increased the protein level of Bcl-2, and decreased the expression levels of Bax and caspase-3 in myocardial tissue by ELISA, compared to those in ADR-induced group. Furthermore, ADR stimulation induced the increased protein levels of TGF-β1 and SMAD2/3/4, the increased phosphorylation levels of SMAD2/3 and the reduced protein levels of SMAD7. The expression levels of protein above in ADR-induced group were remarkably reversed in PAP-3.2KD-treated groups. PAP-3.2KD ameliorated ADR-induced myocardial injury by regulating the TGF-β/SMAD signaling pathway. Thus, these results provide a strong rationale for the protective effects of PAP against ADR-induced myocardial injury, when ADR is used to treat cancer.
研究领域:
药理学
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心脏病学
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传统中药
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分子生物学
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DOI
PubMed
高影响因子
Genes
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2024
·Vol. 15
·期 12
·1575
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IF 2.8
Dandan Wu,Xinning Sun,Xin Li,Zongchao Zuo,Dong Yan,Wu Yin
Background: Hepatocellular carcinoma (HCC) is a type of malignant tumor with high morbidity and mortality. Untimely treatment and high recurrence are currently the major challenges for HCC. The identification of potential targets of HCC progression is crucial for the development of new therapeutic strategies. Methods: Bioinformatics analyses have been employed to discover genes that are differentially expressed in clinical cases of HCC. A variety of pharmacological methods, such as MTT, colony formation, EdU, Western blotting, Q-PCR, wound healing, Transwell, cytoskeleton F-actin filaments, immunohistochemistry (IHC), hematoxylin–eosin (HE) staining, and dual-luciferase reporter assay analyses, were utilized to study the pharmacological effects and potential mechanisms of ribonucleotide reductase regulatory subunit M2 (RRM2) in HCC. Results: RRM2 expression is significantly elevated in HCC, which is well correlated with poor clinical outcomes. Both in vitro and in vivo experiments demonstrated that RRM2 promoted HCC cell growth and metastasis. Mechanistically, RRM2 modulates the EMT phenotype of HCC, and further studies have shown that RRM2 facilitates the activation of the TGF-β/Smad signaling pathway. SB431542, an inhibitor of TGF-β signaling, significantly inhibited RRM2-induced cell migration. Furthermore, RRM2 expression was correlated with diminished survival in HBV-associated HCC patients. RRM2 knockdown decreased the levels of HBV RNA, pgRNA, cccDNA, and HBV DNA in HepG2.2.15 cells exhibiting sustained HBV infection, while RRM2 knockdown inhibited the activity of the HBV Cp, Xp, and SpI promoters. Conclusion: RRM2 is involved in the progression of HCC by activating the TGF-β/Smad signaling pathway. RRM2 increases HBV transcription in HBV-expressing HCC cells. Targeting RRM2 may be of potential value in the treatment of HCC.
研究领域:
肿瘤学
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分子生物学
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肝脏病学
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DOI
PubMed
高影响因子
Cell Reports Medicine
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2025
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IF 10.6
Shuai Yang,Xinyao Qiu,Yingcheng Yang,Jing Wu,Shan Wang,Bo Zheng,Jianmin Wu,Tao Zhou,Yangqianwen Zhang,Mixue Bai,Shuowu Liu,Zihan Zhao,Yani Zhang,Yixian Wang,Jinxia Bao,Mengye Wu,Dongdong Xue,Meiyu Bao,Ji Hu,Siyun Shen,Hongyang Wang,Lei Chen
Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206 + macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.
研究领域:
肿瘤学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
INFLAMMATION
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2023
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IF 5.1
Huang Yina,Zhang Lu,Tan Lingping,Zhang Chi,Li Xiting,Wang Panpan,Gao Li,Zhao Chuanjiang
Periodontitis is a chronic inflammatory disease characterized by the destruction of tooth-supporting tissues. The gingival epithelium is the first barrier of periodontal tissue against oral pathogens and harmful substances. The structure and function of epithelial lining are essential for maintaining the integrity of the epithelial barrier. Abnormal apoptosis can lead to the decrease of functional keratinocytes and break homeostasis in gingival epithelium. Interleukin-22 is a cytokine that plays an important role in epithelial homeostasis in intestinal epithelium, inducing proliferation and inhibiting apoptosis, but its role in gingival epithelium is poorly understood. In this study, we investigated the effect of interleukin-22 on apoptosis of gingival epithelial cells during periodontitis. Interleukin-22 topical injection and Il22 gene knockout were performed in experimental periodontitis mice. Human gingival epithelial cells were co-cultured with Porphyromonas gingivalis with interleukin-22 treatment. We found that interleukin-22 inhibited apoptosis of gingival epithelial cells during periodontitis in vivo and in vitro , decreasing Bax expression and increasing Bcl-xL expression. As for the underlying mechanisms, we found that interleukin-22 reduced the expression of TGF-β receptor type II and inhibited the phosphorylation of Smad2 in gingival epithelial cells during periodontitis. Blockage of TGF-β receptors attenuated apoptosis induced by Porphyromonas gingivalis and increased Bcl-xL expression stimulated by interleukin-22. These results confirmed the inhibitory effect of interleukin-22 on apoptosis of gingival epithelial cells and revealed the involvement of TGF-β signaling pathway in gingival epithelial cell apoptosis during periodontitis.
研究领域:
牙科学
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免疫学
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细胞生物学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2025
·Vol. 32
·期 1
·1-12
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IF 3.5
Lijuan Liang,Zhiheng Dong,Ziqing Shen,Yifan Zang,Wenlong Yang,Lan Wu,Lidao Bao
Hepatic fibrosis (HF) is a critical marker of advanced‑stage chronic liver disease and involves pivotal contributions from hepatic stellate cells (HSCs). Currently, there are no effective treatments for HF. Umbelliferone (7‑hydroxycoumarin; UMB) is a natural compound with significant anti‑inflammatory, antioxidant and anti‑tumor activities. However, its potential efficacy in treating HF has not been studied. The present study explored the protective effects of UMB against HF, targeting the TGF‑β1‑Smad signaling pathway to explore the underlying mechanisms of UMB. Carbon tetrachloride (CCl4) was injected intraperitoneally to induce HF in rats and primary HSCs were treated in vitro with UMB to investigate the improvement effect of UMB on HF. The levels of fibrosis markers, inflammation, oxidative stress and TGF‑β1‑Smad signaling pathway in the rat liver tissue and HSCs were detected using hematoxylin and eosin staining, enzyme‑linked immunosorbent assay, reverse transcription‑quantitative PCR, Cell Counting Kit‑8 and western blotting. The improvement in liver histopathology, liver function indexes and fibrosis markers demonstrated that UMB markedly inhibited the CCl4‑induced HF and inflammation in the rats. Additionally, UMB prominently reduced the pro‑inflammatory factors and oxidative stress levels. In vitro, UMB markedly inhibited primary HSC activation and decreased alpha‑smooth muscle actin and collagen I expression. The mechanism experiment proved that UMB inhibited the TGF‑β1‑Smad signaling pathway and ameliorated HF. The present study was the first to demonstrate, to the best of the authors' knowledge, that UMB might be a promising natural active compound for treating HF. Its therapeutic effect is associated with its modulation of the TGF‑β1‑Smad signaling pathway.
研究领域:
药理学
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肝脏病学
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DOI
PubMed
高影响因子
Applied Biological Chemistry
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2024
·Vol. 67
·期 1
·1-11
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IF 2.3
Yu Ziqing,He Wen,Shi Weiwu
All chronic renal disorders eventually lead to renal interstitial fibrosis (RIF). Chronic inflammation and pro-fibrotic substances are familiar companions of the fibrotic process. The Sulforaphane (Sul) molecule is particularly useful in protecting the liver from oxidative damage. To investigate the Sul effects on fibrosis markers and inflammatory proteins in the kidney of NRK52E cell line and rats and clarify the mechanism of TGF-β/Smad signaling pathway in a rat model of RIF were developed in the present study. Sul (50, 100, and 200 ng/ml) remarkably reduced the gene expressions of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin (IL)-1β, collagen 3 (COL3A1), collagen 1 (COL1A1), and α-smooth muscle actin (α-SMA) in fibrotic NRK52E cells compared with those in cells inspired by transforming growth factor-α (TGF-α). Histopathological investigations showed that Sul administration retained renal tissue structure and decreased kidney tissue fibrosis in rats subjected to unilateral ureteral blockage (UUO). The expression level of TNF-α, IL-6, IL-1β, COL3A1, COL1A1, and α-SMA in the rats’ kidneys exposed to UUO was also suppressed by the treatment of Sul. In the present study, western blot analysis showed that Sul upregulated the expressions of fibrotic NRK52E cells Smad7 and rat model UUO groups while simultaneously decreasing the stimulation of Smad2/3 and the expressions of cyclooxygenase-2, NF-κB, Smad4, activator protein-1, and high-mobility group protein B1. Ultimately, Sul’s ability to inhibit the TGF-β/Smad pathway and the development of inflammation factors may mitigate RIF.
研究领域:
医学
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药理学
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分子生物学
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DOI
高影响因子
EUROPEAN JOURNAL OF IMMUNOLOGY
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2024
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IF 4.5
Caiying Wang,Yue Zhang,Yabin Lu,Xin Huang,Huazheng Jiang,Guohui Chen,Yongheng Shao,Huub F.J. Savelkoul,Christine A. Jansen,Guangliang Liu
Secretory IgA is crucial for preventing the invasion of entero-pathogens via intestinal mucosa. While it is well-established that Transforming growth factor β1 (TGF-β1) regulates IgA production in human and mouse B cells, our previous investigation revealed different functions of TGF-β1 in IgA generation in pigs compared with humans and mice, with the underlying mechanism remaining elusive. In this study, IgM + B cells from porcine Peyer's patches (PPs) were isolated and stimulated with recombinant porcine TGF-β1 to evaluate the effect of TGF-β1 on pigs. The results showed that antibody production from B cells of PPs was impaired by TGF-β1 ex vivo. Furthermore, TGF-β1 treatment led to a decrease in the expression of germ-line transcript αand postswitch transcript α. Moreover, we observed that TGF-β1 predominantly inhibited the phosphorylation of p38-mitogen-activated protein kinases (MAPK), confirming the involvement of the p38-MAPK pathway in porcine IgA generation and IgA class switch recombination. The application of p38-MAPK inhibitor resulted in decreased B-cell differentiation levels. Collectively, this study demonstrates that exogenous TGF-β1 restrains the production and class switch recombination of IgA antibodies by inhibiting p38-MAPK signaling in porcine PPs B cells, which may constitute a component of TGF-β1-mediated inhibition of B-cell activation.
研究领域:
免疫学
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分子生物学
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兽医学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Younan Ren,Ying Chen,Emily H. Tang,Yixin Hu,Bo Niu,Huaduan Liang,Chuchu Xi,Fang Zhao,Zhengyu Cao
Chronic liver diseases (CLD) impact over 800 million people globally, causing about 2 million deaths annually. Arbidol (ARB), an indole-derivative used to treat influenza virus infection, was extensively used during COVID-19 pandemic in China. In recent years, studies have shown that ARB, compared to other antiviral drugs, exhibits greater liver-protective efficacy, indicating a potential hepatoprotective effect beyond its antiviral activity. However, the mechanism remains unclear. In this study, we investigated the impact of ARB on liver injury/fibrosis in bile duct ligated (BDL) mice and its effect on spontaneous and transforming growth factor β1 (TGF-β1)-induced activation of primary cultured hepatic stellate cells (HSCs). Oral administration of ARB significantly ameliorated BDL-induced liver injury/fibrosis as reflected by decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), reduced collagen deposition, and diminished mRNA expression of fibrosis markers. ARB notably inhibited spontaneous and TGF-β1-induced activation of primary cultured HSCs. Moreover, ARB also drastically attenuated mRNA expression levels of platelet-derived growth factor receptor ( Pdgfr), transforming growth factor-beta receptor ( Tgfbr ) 1, Tgfbr2, matrix metalloproteinase (Mmp)-2, and Mmp-9 in activated HSCs. We further demonstrate that ARB mitigated Smad2/3 phosphorylation in both TGF-β1 treated HSCs and BDL mice. These data together demonstrate that the therapeutic efficacy of ARB on liver fibrosis is independent of its antiviral activity and likely is achieved by blocking TGF-β1 signaling-mediated HSC activation.
研究领域:
药理学
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肝病学
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分子生物学
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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
Peizhi Jia,Daxin Chen,Ying Zhu,Meiling Wang,Jianwei Zeng,Ling Zhang,Qiaoyan Cai,Dawei Lian,Chunyu Zhao,Yaoyao Xu,Jianfeng Chu,Shan Lin,Jun Peng,Wei Lin
Ethnopharmacological relevance Liensinine(Lien, C 37 H 42 N 2 O 6 ) is an alkaloid compound from plumula nelumbinis that demonstrates an antihypertensive effect. The protective effects of Lien on target organs during hypertension are still unclear. Aim of the study : This study aimed to understand the mechanism of Lien during the treatment of hypertension, with emphasis on vascular protection. Materials and methods Lien was extracted and isolated from plumula nelumbinis for further study. In vivo model of Ang II-induced hypertension, non-invasive sphygmomanometer was used to detect the blood pressure in and out of the context of Lien intervention. Ultrasound was used to detect the abdominal aorta pulse wave and media thickness of hypertensive mice, and RNA sequencing was used to detect the differential genes and pathways of blood vessels. The intersection of Lien and MAPK protein molecules was detected by molecular interconnecting technique. The pathological conditions of abdominal aorta vessels of mice were observed by HE staining. The expression of PCNA, α-SMA, Collagen Type Ⅰ and Collagen Type Ⅲ proteins were detected by IHC. The collagen expression in the abdominal aorta was detected by Sirius red staining. The MAPK/TGF-β1/Smad2/3 signaling and the protein expression of PCNA and α-SMA was detected by Western blot. In vitro , MAPK/TGF-β1/Smad2/3 signaling and the protein expression of PCNA and α-SMA were detected by Western blot, and the expression of α-SMA was detected by immunofluorescence; ELISA was used to detect the effect of ERK/MAPK inhibitor PD98059 on Ang Ⅱ-induced TGF-β1secrete; and the detection TGF-β1and α-SMA protein expression by Western blot; Western blot was used to detect the effect of ERK/MAPK stimulant12-O-tetradecanoyl phorbol-13-acetate (TPA) on the protein expression of TGF-β1 and α-SMA. Results Lien displayed an antihypertensive effect on Ang Ⅱ-induced hypertension, reducing the pulse wave conduction velocity of the abdominal aorta and the thickness of the abdominal aorta vessel wall, ultimately improving the pathological state of blood vessels. RNA sequencing further indicated that the differential pathways expressed in the abdominal aorta of hypertensive mice were enriched in proliferation-related markers compared with the Control group. The profile of differentially expressed pathways was ultimately reversed by Lien. Particularly, MAPK protein demonstrated good binding with the Lien molecule. In vivo, Lien inhibited Ang Ⅱ-induced abdominal aorta wall thickening, reduced collagen deposition in the ventral aortic vessel, and prevented the occurrence of vascular remodeling by inhibiting MAPK/TGF-β1/Smad2/3 signaling activation. In addition, Lien inhibited the activation of Ang II-induced MAPK and TGF-β1/Smad2/3 signaling, attenuating the expression of PCNA and inhibiting the reduction of α-SMA, collectively playing a role in the inhibition of Ang Ⅱ-induced hypertensive vascular remodeling. PD98059 alone could inhibit Ang Ⅱ-induced elevation of TGF-β1 and the decrease of α-SMA expression. Further, PD98059 combined with Lien had no discrepancy with the inhibitors alone. Simultaneously TPA alone could significantly increase the expression of TGF-β1 and decrease the expression of α-SMA. Further, Lien could inhibit the effect of TPA. Conclusion This study helped clarify the protective mechanism of Lien during hypertension, elucidating its role as an inhibitor of vascular remodeling and providing an experimental basis for the research and development of novel antihypertensive therapies.
研究领域:
药理学
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心血管疾病
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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
FOOD AND CHEMICAL TOXICOLOGY
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2025
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IF 3.5
Yongjun Tang,Zhengning Feng,Chenlu Ma,Nian Jang,Xiaolong Chen,Yingxu He,Francis L. Martin,Hui Liu,Weiyi Pang
Breast cancer has a high global incidence, and benzo[ a ]pyrene (B[ a ]P) is considered a contributing factor that increases carcinogenic risk. This study examined B[ a ]P's oncogenic mechanisms in mammary epithelial cells. Chronic B[ a ]P exposure induced morphological changes and enhanced proliferative/clonogenic capacity in MCF-10A cells. Chronic B[ a ]P exposure altered gene expression in MCF-10A cells, revealing differential levels of circRNAs, lncRNAs, miRNAs, and mRNAs. qRT-PCR validation demonstrated strong alignment with RNA-seq results, ensuring sequencing reliability. Additionally, chronic B[ a ]P exposure upregulated the protein expression of AhR and ARNT, as well as TGF- β , pSmad2/3, and KRT14 , while increasing Vimentin expression and decreasing E-cadherin expression. Notably, treatment with the TGF- β inhibitor SB431542 reversed these protein expression changes in transformed cells. These results show that exposure to Chronic B[ a ]P induces MCF-10A cell transformation. The underlying mechanisms involve significant transcriptional alterations, AhR/ARNT expression regulation, TGF- β signaling pathway activation, KRT14 protein modulation, and EMT. Furthermore, Chronic B[ a ]P exposure may drive transformation through TGF- β modulation. Chronic B[ a ]P exposure promotes breast carcinogenesis, revealing mechanistic insights and potential preventive biomarkers.
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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产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2023
·Vol. 69
·期 9
·
IF 1.6
Aili Xuan,Mei Yang,Qun Xia,Qian Sun
Asthma is a respiratory inflammatory disease, and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is involved in the progression of respiratory diseases. However, the role of NOX4 in asthma remains unclear. In the present study, we aimed to explore the effects of NOX4 on airway remodeling and inflammation. NOX4 expression was measured using immunocytochemistry (IHC), western blot, and real-time PCR (qPCR). Lung tissues were stained using the H&E assay. ELISA was used to examine the levels of airway remodeling-related indicators, and qPCR was used to detect airway inflammatory factors. The results indicated that NOX4 is highly expressed in lung tissues, bronchoalveolar lavage fluid (BALF), and serum of OVA-treated mice. Inhibition of NOX4 alleviated OVA-induced airway remodeling and inflammation. Similarly, TGF-β1 was also upregulated in BALF and serum OVA-induced mice. Inhibition of TGF-β1 signaling also improved airway remodeling and inflammation induced by OVA. Moreover, the downregulation of NOX4 inactivated the TGF-β1-Smad2/3 pathway, and TGF-β1 decreased Smad2/3 expression. Moreover, inhibition of the TGF-β1 was enhanced, while TGF-β1 reversed the effects on airway remodeling and inflammation induced by NOX4 inhibition. Taken together, the downregulation of NOX4 improves airway remodeling and inflammation via inactivation of the TGF-β1-Smad2/3 pathway in asthma mice, suggesting that NOX4 may be a therapeutic target for asthma.
研究领域:
呼吸系统疾病
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
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