BIOORGANIC CHEMISTRY
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2025
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IF 4.7
Nan Li,Feng-xiang Pang,Yu-wan Zhou,Shou-chang Ding,Chuan-jian Shi,Rui-jia Wen,Yong-xin Mai,Xian-lin Wu,Jin-fang Zhang
Background Osteosarcoma (OS) is a malignant primary tumor in bone tissues, and Methotrexate (MTX) is widely used as a chemotherapeutic drug for OS in clinical treatment. However, MTX resistance is a major challenge for OS patients. Polydatin (PD) is an extract derived from Reynoutria japonica Houtt and has been identified as a potential agent for reversing chemotherapy resistance in cancer. We therefore wondered whether PD could alleviate MTX resistance in OS. Methods The effect of PD on MTX resistance was investigated. And H19 expression was examined in the PD-treated OS cells. The association between H19 and MTX resistance in osteosarcoma was investigated.The effects of H19 on MTX resistance in osteosarcoma were evaluated by cell proliferation, colony formation, ChIP and western blotting assays. In order to investigate the molecular mechanism of PD underlying methotrexate resistance in OS, the cell proliferation, colony formation, q-PCR and western blotting were examined. Results In the present study, PD was found to act as a novel MTX sensitizer, and significantly enhanced the suppressive effects of MTX on OS in vitro and in vivo . Mechanically, PD was demonstrated to suppress the expression of long non-coding RNA H19 as well as its binding protein histone methyltransferase Enhancer of zeste homolog 2 (EZH2), and thus reduced the trimethylation of histone H3K9 (H3K9me3) and K27 (H3K27me3). Furthermore, H19 knowndown increased the binding ability of H3K9me3 and H3K27me3 with the folate metabolism-related genes RFC-1 and PCFT's promoter, and influenced folate metabolism and MTX resistance. Conclusion In conclusion, our results indicated that PD alleviated MTX resistance in OS via the H19/H3K27me3/H3K9me3 mediated folate metabolism regulatory axis. The translational potential of this article The findings of this study validate the function of PD in alleviating MTX resistance, and provide the new insight into developing PD as a promising drug candidate for the MTX resistant OS patients.
研究领域:
肿瘤学
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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 Orthopaedic Translation
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2023
·
IF 6.6
Fengxiang Pang,Shouchang Ding,Nan Li,Zhipeng Li,Nannan Tian,Chuanjian Shi,Fengwei Zhang,Yongxin Mai,Jinfang Zhang,Junyan Wang
Background Osteosarcoma (OS) is the most common primary malignancy in bone tissues, and effective therapeutics remain absent in clinical practice. Traditional Chinese medicines (TCM) have been used for thousands of years, which provide great insights into OS management. Gallic acid (GA) is a natural phenolic acid enriched in various foods and herbs. Several pharmacological activities of GA such as anti-oxidation and anti-inflammation have been well-established. However, its biological function in OS remains not fully understood. Methods The potential anti-cancer properties of GA were evaluated in 143 B, U2OS and MG63 cells. Its effects on cell growth, cell cycle, apoptosis and migration were examined in these OS cells. The lncRNA H19 and Wnt/β-catenin signaling were detected by qPCR, luciferase activity and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using an orthotopic mouse model. Results In the present study, GA was found to suppress the tumor growth in vitro via inducing cell cycle arrest and apoptosis in OS cells, and inhibit the invasion and metastasis as well. Using the orthotopic animal model, GA was also found to suppress tumorigenesis in vivo . Long noncoding RNA (lncRNA) H19 was demonstrated to be down-regulated by GA, and thus disrupted the canonical Wnt/β-catenin signaling in OS cells. Furthermore, the ectopic expression of H19 rescued the GA-induced suppressive effects on tumor growth and metastasis, and partially reversed the inactivation of Wnt/β-catenin signaling. Conclusions Taken together, our results indicated that GA inhibited tumor growth through an H19-mediated Wnt/β-catenin signaling regulatory axis in OS cells. The translational potential of this article The information gained from this study provides a novel underlying mechanism of GA mediated anti-OS activity, suggesting that GA may be a promising drug candidate for OS patients.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2020
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IF 3.943
Zhi-Min Wang,Si-Wei Xia,Tian Zhang,Zhen-Yi Wang,Xiang Yang,Jun Kai,Xu-Dong Cheng,Jiang-Juan Shao,Shan-Zhong Tan,An-Ping Chen,Shi-Jun Wang,Feng Zhang,Zi-Li Zhang,Shi-Zhong Zheng
Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by enhanced retinoic acid signals. Although up-regulated retinoic acid signal responds further to maintain HSC activation, the underlying molecular mechanisms are largely unknown. In this study, we sought to investigate the role of lncRNA-H19 in regulation of retinoic acid signals, and to further examine the underlying mechanism in this molecular context. We found that lncRNA-H19 upregulation could enhance retinoic acid signals to induce HSC activation, whereas lncRNA-H19 knockdown completely disturbed retinoic acid signals. Moreover, the activation of retinoic acid signals impaired the lncRNA-H19 knockdown mediated HSC inactivation. Interestingly, we also found that enhanced retinoic acid signals by lncRNA-H19 was associated with a coordinate increase in retinol metabolism during HSC activation. Increased retinol metabolism contributed to obvious lipid droplet consumption. Importantly, we identified that alcohol dehydrogenase III (ADH3) was essential for lncRNA-H19 to enhance retinoic acid signals. The inhibition of ADH3 completely abrogated the lncRNA-H19 mediated retinoic acid signals and HSC activation. Of note, we identified dihydroartemisinin (DHA) as a natural inhibitor for lncRNA-H19. Treatment with DHA significantly decreased the expression of lncRNA-H19, reduced the expression of ADH3, blocked retinoic acid signals, and in turn, inhibited HSC activation. Overall, these results provided novel implications to reveal the molecular mechanism of increased retinoic acid signals during HSC activation, and identify lncRNA-H19/ADH3 pathway as a potential target for the treatment of liver fibrosis.
研究领域:
分子生物学
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肝病学
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药理学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2020
·
IF 3.263
Fei-fei Pan,Yan-Biao Zheng,Chuan-Jian Shi,Feng-wei Zhang,Jin-fang Zhang,Wei-ming Fu
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. However, the effective pharmacological approaches remain scanty in clinical practice. As a bioactive flavonoid , apigenin (API) is enriched in common fruits and vegetables. Although pharmacological activities of API have been widely investigated, its biological function in HCC remains obscure. In the present study, we found that API strongly suppressed cell growth and induced apoptosis in HCC cells. Using a xenograft mice model, API was demonstrated to inhibit the in vivo tumor growth. It is known that the long non-coding RNA H19, which is frequently elevated in HCC, plays a vital role in mediating tumorigenesis and cancer progression. Our results demonstrated that H19 was down-regulated by API, and thereby induced the inactivation of the canonical Wnt/β-catenin signaling. In conclusion, our results demonstrated that API was able to suppress tumor growth of HCC through H19-mediated Wnt/β-catenin signaling regulatory axis, suggesting that API may be a promising candidate for developing novel therapeutic approaches against liver cancer.
研究领域:
肿瘤学
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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
BMC Complementary Medicine and Therapies
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2021
·Vol. 21
·期 1
·1-12
·
IF 0
Bian Wei,Xiao Shunqiang,Yang Lei,Chen Jun,Deng Shifang
Background Quercetin and H19 can promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). However, whether quercetin regulates H19 expression to promote osteogenic differentiation of BMSCs is unclear.Methods BMSC proliferation, matrix mineralization, and alkaline phosphatase (ALP) activity were assessed using the Cell Counting Kit-8, ALP assay kit, and alizarin red staining kit, respectively. Expression of H19, miR-625-5p, BMP-2, osteocalcin, and RUNX2 were measured by qRT-PCR; β-catenin protein level was measured by western blotting.Results Quercetin promoted BMSC proliferation, enhanced ALP activity, and upregulated the expression of BMP-2, osteocalcin, and RUNX2 mRNAs, suggesting that it promoted osteogenic differentiation of BMSCs. Moreover, quercetin increased H19 expression, while the effect of quercetin on BMSCs was reversed by silencing H19 expression. Additionally, miR-625-5p, interacted with H19, was downregulated during quercetin-induced BMSC osteogenic differentiation, which negatively correlated with H19 expression. Silencing miR-625-5p expression promoted BMSC proliferation and osteogenic differentiation, whereas miR-625-5p overexpression weakened the effect of quercetin on BMSCs. Finally, quercetin treatment or downregulation of miR-625-5p expression increased β-catenin protein level in BMSCs. Upregulation or downregulation of miR-625-5p or H19 expression, respectively, inhibited β-catenin protein level in quercetin treated-BMSCs.Conclusion H19 promotes, while miR-625-5p inhibits BMSC osteogenic differentiation. Quercetin activates the Wnt/β-catenin pathway and promotes BMSC osteogenic differentiation via the H19/miR-625-5p axis.
研究领域:
分子生物学
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干细胞研究
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骨骼生物学
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DOI
PubMed
CHEMOSPHERE
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2020
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IF 5.778
Jing Li,Xiao-jie Quan,Gang Chen,Jia-wei Hong,Qi Wang,Lin-lin Xu,Bing-hua Wang,Ze-hua Yu,Hong-Min Yu
Perfluorooctane sulfonic acid (PFOS), a persistent environmental pollutant, has been associated with decreased birth weight. The dysregulation of long non-coding RNA (lncRNA) H1 9 has been implicated in pregnancy complications such as intra-uterine growth retardation (IUGR), preeclampsia (PE), however, the expression and function of H19 in PFOS-exerted detrimental effects in the placenta remains to be unveiled. Here, we explored the role of H19 in PFOS-induced placental toxicity. Results showed that PFOS caused decreased cell growth in human HTR-8/SVneo cells. Expression of H19 was increased, while miR-19a and miR-19b expression were decreased in mice placenta tissues and in HTR-8/SVneo cells exposed to PFOS. A significant hypomethylation was observed at the H19 promoter in the placentas of mice that were gestational exposed to high dose of PFOS. H19 was confirmed to bind with miR-19a and miR-19b, targeting SMAD4 . Furthermore, H19 appeared to partially improve the cell growth of HTR-8/SVneo cells exposed to PFOS via upregulation of miR-19a and miR-19b. In summary, our findings revealed that H1 9/miR-19a and miR-19b/SMAD4 axis exerted important functions in PFOS-induced placenta cell toxicity.
研究领域:
毒理学
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分子生物学
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生殖健康
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2021
·
IF 4.432
Feiran Zhou,Xinyi Hu,Weijing Feng,Minghui Li,Bin Yu,Chenxing Fu,Caiwen Ou
Intimal hyperplasia-induced restenosis is a common response to vascular endothelial damage caused by mechanical force or other stimulation, and is closely linked to vascular remodeling . Curcumin , a traditional Chinese medicine , exhibits potent protective effects in cardiovascular diseases; for example, it attenuates vascular remodeling. Although the suppressive effects of curcumin on diseases caused by vascular narrowing have been investigated, the underlying mechanisms remain unknown. Long non-coding RNAs (lncRNAs) regulate various pathological processes and affect the action of drugs. In the present study, we found that the curcumin remarkably downregulated the expression of lncRNA H19 and thereby inhibited intimal hyperplasia-induced vascular restenosis. Furthermore, the inhibition of the expression of H19 by curcumin resulted in the inactivation of the Wnt/β-catenin signaling. Overall, we show that curcumin suppresses intimal hyperplasia via the H19/Wnt/β-catenin pathway, implying that H19 is a critical molecule in the suppression of intimal hyperplasia after balloon injury by curcumin. These insights should be useful for potential application of curcumin as a therapeutic intervention in vascular stenosis.
研究领域:
分子生物学
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药理学
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心血管疾病
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DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2021
·Vol. 36
·期 8
·2461-2472
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IF 3.584
Huang Yuxing,Deng Lisha,Zeng Lin,Bao Shanlin,Ye Kun,Li Chengxun,Hou Xiaolin,Yao Yuan,Li Dingjun,Xiong Zhen
Cerebral ischemia/reperfusion (I/R) injury remains a leading cause of death and disability. Long noncoding RNAs (lncRNAs) exert key functions in cerebral I/R injury. Here, we sought to elucidate the mechanism underlying the regulation of H19 in cerebral I/R cell injury. An in vitro model of cerebral I/R injury was created using oxygen–glucose deprivation/reoxygenation (OGD/R). The levels of H19, miR-1306-5p and B cell lymphoma-2 (Bcl-2)-like 13 (BCL2L13) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell viability and apoptosis were determined by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. The levels of lactate dehydrogenase (LDH) and cytokines were evaluated by enzyme-linked immunosorbent assays (ELISA). Direct relationships among H19, miR-1306-5p and BCL2L13 were verified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pulldown assays. Our data showed that H19 and BCL2L13 were highly expressed in the cerebral I/R injury rats and OGD/R-triggered SK-N-SH and IMR-32 cells. The knockdown of H19 or BLC2L13 alleviated OGD/R-triggered injury in SK-N-SH and IMR-32 cells. Moreover, H19 silencing protected against OGD/R-triggered cell injury by down-regulating BCL2L13. H19 acted as a sponge of miR-1306-5p and BCL2L13 was a direct target of miR-1306-5p. H19 mediated BCL2L13 expression by sequestering miR-1306-5p. Furthermore, miR-1306-5p was a molecular mediator of H19 function. These results suggested that H19 silencing alleviated OGD/R-triggered I/R injury at least partially depending on the regulation of the miR-1306-5p/BCL2L13 axis.
研究领域:
神经科学
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分子生物学
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细胞生物学
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医学研究
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DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
·
2024
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IF 4
Jiaorong QU,Xiaoyong XUE,Zhixing WANG,Zhi MA,Kexin JIA,Fanghong LI,Yinhao ZHANG,Ruiyu WU,Fei ZHOU,Piwen ZHAO,Xiaojiaoyang LI
ABSTRACT Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix (ECM). Si-Wu-Tang (SWT), a traditional Chinese medicine (TCM) formula, is known for treating gynecological diseases and liver fibrosis. Our previous studies demonstrated that long non-coding RNA H19 (H19) was markedly upregulated in fibrotic livers while its deficiency markedly reversed fibrogenesis. However, the mechanisms by which SWT influences H19 remain unclear. Thus, we established a bile duct ligation (BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the liver. Our results showed that SWT markedly improved ECM deposition and bile duct reactions in the liver. Notably, SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling, primarily in hepatic stellate cells (HSCs), and influencing cytoskeleton-related angiogenesis and hepatocellular injury. This modulation collectively led to reduced ECM deposition. Through extensive bioinformatics analyses, we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200, miR-211, and let7b, thereby regulating the above cellular regulatory pathways. Meanwhile, SWT reversed H19-related miRNAs and signaling pathways, diminishing ECM deposition and liver fibrosis. However, these protective effects of SWT were diminished with the overexpression of H19 in vivo . In conclusion, our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.
研究领域:
药理学
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分子生物学
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肝病学
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传统中药
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DOI
PubMed
高影响因子
Journal of Advanced Research
·
2025
·
IF 13
Yajing Li,Runping Liu,Jianan Li,Feng Gao,Zhi Ma,Kaihong Xie,Fanghong Li,Bing Xu,Qi Zheng,Yajie Cai,Jiaorong Qu,Xiaoyong Xue,Kexin Jia,Xiaojiaoyang Li
Introduction Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. Objective: This study aims to unveil the underlying mechanisms of the protective effects of senkyunolide A (SenA) on cholangiocyte overproliferation in cholestatic liver diseases. Methods : Through comprehensive characterization using RNA sequencing, CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we explored the effects and mechanisms of SenA in vivo in bile duct ligation mice and in vitro in primary cholangiocytes. Results : We demonstrated that SenA effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19, Let-7a and Lin28a. Mechanically, we identified a potential interaction between the carbonyl group in SenA and Arg483 in TRAF6, disrupting the TRAF6-HDAC3 complex. This dissociation facilitates the binding of HDAC3 to the MYC promoter region, resulting in enhanced histone deacetylation and transcriptional suppression. Conclusion : We highlight the therapeutic potential of SenA in cholestatic liver diseases by elucidating its role in epigenetic regulation.
研究领域:
医学
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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
INTERNATIONAL DENTAL JOURNAL
·
2026
·Vol. 76
·期 4
·109587
·
IF 5.2
Jingkun Zhang,Li Lin,Huixian Dong,Bingtao Wang,Xiaoshi Chen,Chenhao Wang,Liecong Lin,Jialin Zhong,Guocong Zheng,Qianzhou Jiang
Background The regeneration of functional dentin is a critical clinical goal for preserving tooth vitality after injury, with odontoblastic differentiation of human dental pulp stem cells (hDPSCs) being central to this reparative process. While the long noncoding RNA H19 is recognised as a key regulator of dentin repair, its downstream regulatory network is complex and incompletely mapped. Beyond the previously established H19/miR-140-5p/BMP2 axis, this study identifies a distinct and parallel pathway in which H19 promotes odontoblastic differentiation by downregulating miR-103a-3p, which in turn targets the PIK3R1/AKT and KLF4 signalling cascades. Our findings reveal that these two downstream networks operate independently, further elucidating the multifaceted role of H19 in dentin regeneration. Methodology In this study, we used lentiviral vectors to stably overexpress H19 in hDPSCs. Bioinformatic analysis and dual-luciferase reporter assays were employed to validate the interactions between H19 and miR-103a-3p, as well as between miR-103a-3p and its target mRNAs, including phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and Kruppel-like factor 4 (KLF4). And qPCR and Western blot were used to investigate the expression pattern of H19 and the potential signalling axis of H19 and key odontogenic markers. Then, alkaline phosphatase and alizarin red S staining were used to evaluate odontogenic differentiation capacity. Finally, a heterotopic pulp regeneration model was established. And HE staining, Masson staining, immunofluorescence and immunohistochemistry were performed to verify the mechanism of H19 regulating odontogenic differentiation in vivo. Results In vitro , H19 promoted odontogenic differentiation of hDPSCs, while miR-103a-3p inhibited them. Both PIK3R1 and KLF4 were identified as direct targets of miR-103a-3p. Ectopic expression of either PIK3R1 or KLF4 restored the odontogenic differentiation capacity of hDPSCs suppressed by miR-103a-3p. Mechanistically, PIK3R1 promoted odontogenesis by activating the PI3K/AKT signalling pathway, whereas KLF4 acted independently as a transcriptional regulator. In vivo , H19 overexpression drove odontoblastic differentiation of hDPSCs by inducing the expression of its downstream targets, PIK3R1 and KLF4. Conclusion Our findings indicated that H19 promoted odontogenic differentiation of hDPSCs by modulating the miR-103a-3p–PIK3R1/AKT and miR-103a-3p–KLF4 axes, underscoring their therapeutic potential for pulp regeneration.
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PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Xueqing Zhou,Xuan Liu,Xiqin Yang,Li Wang,Yiling Hong,Keke Lian,Guoxi Qiu,Xuwei Shang,Zhongjun Ma,Hong Yuan,Fuqiang Hu
Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) play an important role in the development of tumors by secreting a variety of cytokines or directly communicating with tumor cells, making TAMs-targeted therapeutic strategies very attractive. It has been reported that oncogene c-Myc is related to every aspect of the oncogenic process of tumor cells and the alternative activation of macrophages. Hence, we constructed a glycolipid nanocarrier containing ROS-responsive peroxalate linkages (CSOPOSA) for ROS-triggered release of drugs and further modified it with Ex 26 (Ex 26-CSOPOSA), a selective sphingosine 1-phosphate receptor 1 (S1PR1) antagonist, to achieve the dual-targeted delivery of the c-Myc inhibitor JQ1 via S1PR1, which is overexpressed on both tumor cells and TAMs, thereby inducing apoptosis of tumor cells, and blocking M2 polarization of macrophages. More strikingly, our studies found that JQ1 could effectively inhibit the migration of tumor cells induced by M2 macrophages-derived exosomes via blocking Caveolin-1 related intercellular exosome exchange through lncRNA H19 and miR-107. The in vivo results revealed that this dual-targeted delivery strategy effectively inhibited tumor growth and metastasis with less systemic toxicity, providing a potential method for effective tumor treatment.
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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纳米技术
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免疫学
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产品关联
DOI
PubMed
高影响因子
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