Cell and Bioscience
·
2022
·Vol. 12
·期 1
·1-20
·
IF 9.584
Zhang Yufeng,Yang Min,Zhang Sheng,Yang Zhiqiang,Zhu Yufan,Wang Yi,Chen Zhe,Lv Xuan,Huang Zan,Xie Yuanlong,Cai Lin
Background Dysregulated osteoclast activity due to altered osteoclast differentiation causes multiple bone diseases. Osteoclasts are multinucleated giant cells derived from hematopoietic stem cells and play a major role in bone absorption. However, the mechanisms underlying the tight regulation of osteoclast differentiation in multiple pathophysiological status remain unknown. Results We showed that Bhlhe40 upregulation is tightly associated with osteoclast differentiation and osteoporosis. Functionally, Bhlhe40 promoted osteoclast differentiation in vitro, and Bhlhe40 deficiency led to increased bone mass and decreased osteoclast differentiation in vivo. Moreover, Bhlhe40 deficient mice resisted estrogen deficiency and aging-induced osteoporosis. Mechanism study showed that the increase in bone mass due to Bhlhe40 deficiency was a cell intrinsic defect in osteoclast differentiation in these mice. BHLHE40 upregulated the gene expression of Fos and Nfatc1 by directly binding to their promoter regions. Notably, inhibition of Fos/Nfatc1 abrogated the enhanced osteoclast differentiation induced by BHLHE40 overexpression. Conclusions Our research reveals a novel Bhlhe40/c-Fos/Nfatc1 axis involved in regulating osteoclastogenesis and shows that osteoporosis caused by estrogen deficiency and aging can be rescued by regulating Bhlhe40 in mice. This may help in the development of a new strategy for the treatment of osteoporosis.
研究领域:
骨骼生物学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Xiangyun Li,Taoli Sun,Jiaqin Liu,Shanshan Wei,Yuanying Yang,Jian Liu,Bikui Zhang,Wenqun Li
Background Doxorubicin (Dox), a chemotherapeutic agent known for its efficacy, has been associated with the development of severe cardiotoxicity, commonly referred to as doxorubicin-induced cardiotoxicity (DIC). The role and mechanism of action of phloretin (Phl) in cardiovascular diseases are well-established; however, its specific function and underlying mechanism in the context of DIC have yet to be fully elucidated. Objective This research aimed to uncover the protective effect of Phl against DIC in vivo and in vitro , while also providing a comprehensive understanding of the underlying mechanisms involved. Methods DIC cell and murine models were established. The action targets and mechanism of Phl against DIC were comprehensively examined by systematic network pharmacology, molecular docking, transcriptomics technologies, transcription factor (TF) prediction, and experimental validation. Results Phl relieved Dox-induced cell apoptosis in vitro and in vivo . Through network pharmacology analysis, a total of 554 co-targeted genes of Phl and Dox were identified. Enrichment analysis revealed several key pathways including the PI3K-Akt signaling pathway, Apoptosis, and the IL-17 signaling pathway. Protein-protein interaction (PPI) analysis identified 24 core co-targeted genes, such as Fos, Jun, Hif1a, which were predicted to bind well to Phl based on molecular docking. Transcriptomics analysis was performed to identify the top 20 differentially expressed genes (DEGs), and 202 transcription factors (TFs) were predicted for these DEGs. Among these TFs, 10 TFs (Fos, Jun, Hif1a, etc.) are also the co-targeted genes, and 3 TFs (Fos, Jun, Hif1a) are also the core co-targeted genes. Further experiments validated the finding that Phl reduced the elevated levels of Hif3a (one of the top 20 DEGs) and Fos (one of Hif3a's predicted TFs) induced by Dox. Moreover, the interaction between Fos protein and the Hif3a promoter was confirmed through luciferase reporter assays. Conclusion Phl actively targeted and down-regulated the Fos protein to inhibit its binding to the promoter region of Hif3a, thereby providing protection against DIC.
研究领域:
药理学
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分子生物学
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心血管疾病
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肿瘤学
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PubMed
高影响因子
LABORATORY INVESTIGATION
·
2021
·Vol. 101
·期 9
·1118-1129
·
IF 5.662
Wang Xin,Li Xing-Liang,Qin Li-Jie
Myocardial injury is a severe complication of sepsis and contributes substantially to the death of critically ill patients. Long non-coding RNAs (lncRNAs) participate in the pathogenesis of sepsis-induced myocardial injury. In this study, we investigated the role of lncRNA X-inactive specific transcript (XIST) in septic myocardial injury and explored its mechanism. Lipopolysaccharide (LPS)-stimulated H9C2 cells and rats subjected to cecal ligation and puncture (CLP) were used as the in vitro and in vivo models. After exposure to LPS, XIST and c-Fos levels were upregulated, but miR-150-5p was downregulated in H9C2 cardiomyocytes and myocardial tissues. XIST affected viability, apoptosis, and pyroptosis in LPS-challenged H9C2 cells. Moreover, XIST knockdown attenuated LPS-induced injury in H9C2 cells by targeting the miR-150-5p/c-Fos axis. c-Fos could bound to the promoter of the TXNIP/XIST gene and enhanced TXNIP/XIST expression. Silencing of XIST improved cardiac function and survival rate and reduced apoptosis and pyroptosis by regulating the miR-150-5p/c-Fos axis in septic rats in vivo. Taken together, our data show that XIST/miR-150-5p/c-Fos axis affected septic myocardial injury, which may indicate a novel therapeutic strategy for sepsis-induced myocardial injury.
研究领域:
分子生物学
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心脏病学
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传染病学
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药理学
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PubMed
高影响因子
ULTRASOUND IN MEDICINE AND BIOLOGY
·
2020
·
IF 2.514
Yao Liu,Yijin Fan,Huajun Tang,Chengzhi Li
The purpose of this study was to investigate the therapeutic effects of focused ultrasound on the expression of notch1, c-fos and transforming growth factor-β3 (TGF-β3) in genital skin of SD rats with vulvar lichen simplex chronicus (LSC). Fifty-six female SD rats with LSC were randomly divided into therapy and sham groups. The therapy group was exposed to focused ultrasound. The sham group received the same therapy with an instrument that had no power output. Four wk after a singly focused ultrasound therapy, histologic analyses revealed that recovered SD rats accounted for 75% of SD rats in the therapy group and 10.7% in the sham group. Total collagen fiber density in the superficial layer of dermis in the therapy group was significantly lower than that in the sham group. Notch1 and c-fos protein expression in the therapy group was significantly lower than that in the sham group, with the opposite effect present for TGF-β3. Focused ultrasound therapy may inhibit superficial collagen fibrosis in the dermis by affecting expression of notch1, c-fos and TGF-β3 in vulvar skin tissue and consequently reduce the recurrence rate of LSC.
研究领域:
皮肤病学
·
治疗超声
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分子生物学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF ONCOLOGY
·
2022
·Vol. 60
·期 5
·1-14
·
IF 5.884
Hang Sun,Youjie Li,Xiao Wang,Xue Zhou,Simin Rong,Dongmin Liang,Guangbin Sun,Huizhen Cao,Hongfang Sun,Ranran Wang,Yunfei Yan,Shuyang Xie,Yunxiao Sun
Chronic myeloid leukemia (CML) is a hematological disease, and imatinib (IM) resistance represents a major problem for its clinical treatment. In the present study, the role of tribbles pseudokinase 2 (TRIB2) in IM resistance of CML and the possible mechanism were investigated. It was found that TRIB2 was highly expressed in IM‑resistant patients with CML through the Oncomine database and this conclusion was confirmed using reverse transcription‑quantitative PCR and western blot experiments. Knockdown of TRIB2 was found to increase the drug sensitivity of KG cells to IM using Cell‑Counting Kit‑8 (CCK‑8) assays, and the low‑expression TRIB2 mice were further found to be more sensitive to the IM and have a higher survival rate in leukemia model mice. Moreover, using western blot and luciferase experiments, it was found that TRIB2 could regulate c‑Fos through the ERK signaling pathway, and c‑Fos suppressed the transcriptional activity and the expression of miR‑33a‑5p. Further investigation identified that the binding site for c‑Fos to function on miR‑33a‑5p was the ‑958‑965 region. Finally, CCK‑8 assays and western blot experiments demonstrated that miR‑33a‑5p could inhibit the proliferation of KG cells and reduce IM resistance by suppressing the expression of HMGA2. In conclusion, it was demonstrated that TRIB2 regulates miR‑33a‑5p to reverse IM resistance in CML, which may help identify novel targets and therapeutic strategies for the clinical treatment of IM resistance.
研究领域:
肿瘤学
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血液学
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分子生物学
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药理学
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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2024
·
IF 6.1
Wenxuan Liu,Runlin Gui,Yang Li,Man Li,Zhen Lei,Yanyan Jin,Yi Yu,Yujia Li,Lu Qian,Yuyan Xiong
Insulin resistance (IR) is a central pathophysiological process underlying numerous chronic metabolic disorders, including type 2 diabetes and obesity. Lycii Cortex, a widely used traditional Chinese herb, has demonstrated potential benefits in preventing and managing diabetes and IR. Whereas, the specific bioactive compounds responsible for these protective effects and their underlying mechanisms of action remain elusive. This study aimed to identify the bioactive components within Lycii Cortex that contribute to its anti-diabetic effects and to elucidate the molecular mechanisms underlying its beneficial actions on insulin resistance. Network pharmacology and molecular docking analyses were employed to identify the potential active compounds in Lycii Cortex and their corresponding target proteins. An in vitro model of IR was established using palmitic acid (PA)-treated HepG2 cells. Cell viability was assessed using the CCK-8 assay, while glucose uptake was evaluated by 2-NBDG staining and extracellular glucose measurement. To validate the in vitro findings, an in vivo model of obesity-induced IR was established using high-fat diet (HFD)-fed mice. The network pharmacology analysis preliminarily identified 13 candidate chemicals and 10 hub LyC and IR-related genes (LIRRGs). Molecular docking analysis demonstrates that Linarin as the potential active component exhibits the greatest potential to target c-FOS for preventing obesity-induced IR. Enrichment analysis suggested that Linarin-targeted pathways are correlated with inflammation. In vitro experimental validation demonstrated that Linarin was capable of protecting against PA-induced IR in HepG2 cells evidenced by improving glucose uptake ability and reducing extracellular glucose content. Additionally, we found that Linarin ablated PA-induced increase in the expression of c-FOS and inflammatory cytokines. Furthermore, in PA-treated cells, silencing c-FOS markedly improved glucose consumption, and reduced inflammation and Arginase 2 (ARG2) expression. Similarly, as exposure to PA, silencing ARG2 also ameliorated glucose uptake and inflammation, while not affecting c-FOS expression. In vivo experiments further showed that Linarin administration remarkably improved glucose tolerance and insulin sensitivity, and reduced the fat mass and body weight in HFD-induced obese mice. In this study, Linarin has been identified as the bioactive compound of Lycii Cortex to ameliorate obesity-related IR and inflammation through the c-FOS/ARG2 signaling cascade. These findings underscore the therapeutic potential of Linarin and provide valuable insights into developing novel intervention strategies for type 2 diabetes therapy.
研究领域:
药理学
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分子生物学
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内分泌学
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代谢性疾病
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中医药
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DOI
PubMed
高影响因子
PLACENTA
·
2024
·
IF 3
Gaoying Wang,Ruirui Dong,Haijian Zhao,Ningzhen Ye,Jing Wang,Jing Cheng,Xinrui Shi,Liang Luo,Ting Zhang
Background Abnormal bile acid metabolism leading to changes in placental function during pregnancy. To determine whether endoplasmic reticulum protein 29 (ERp29) can mediate the pregnancy effects of cholestasis by altering the level of trophoblast cell apoptosis. Methods ERp29 in serum of 66 intrahepatic cholestasis of pregnancy (ICP) pregnant women and 74 healthy were detected by ELISA. Subcutaneous injection of ethinyl estradiol (E2) was used to induce ICP in pregnant rats. Taurocholic acid (TCA) was used to simulate the ICP environment, and TGF-β1 was added to induce the epithelial mesenchymal transformation (EMT) process. The scratch, migration, and invasion test were used to detect the EMT process. ERp29 overexpression/knockdown vector were constructed and transfected to verify the role of ERp29 in the EMT process. Downstream gene was obtained through RNA-seq. Results Compared with the healthy pregnant women, the expression levels of ERp29 in serum of ICP pregnancy women were significantly increased (P < 0.001). ERp29 in the placenta tissue of the ICP pregnant rats increased significantly, and the level of apoptosis increased. The placental tissues of the ICP had high expression of E-cadherin and low expression of N-cadherin, snail1, vimentin. After HTR-8/SVneo cells were induced by TCA, EMT was inhibited, while the ERp29 increased. Cell and animal experiments showed that, knockdown of ERp29 reduced the inhibition of EMT, the ICP progress was alleviated. Overexpression of FOS salvaged the inhibitory effects of ERp29 on cell EMT. Discussion The high level of ERp29 in placental trophoblast cells reduced FOS mRNA levels, inhibited the EMT process and aggravated the occurrence and development of ICP.
研究领域:
妇产科学
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分子生物学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Lin Wujian,Li Xiance,Hu Wei,Zhao Xiaoyi,Wei Nana,Li Yuying,Bao Qi,Tian Cheng,Liu Weiwei,Chen Zitao,Mai Zilong,Zhao Shuhao,Zhu Yuanyuan,Zhu Guohui,Huang Haibo,Tang Zhonglin
In the livestock industry, intramuscular fat deposition
is a key
factor influencing meat tenderness and flavor. Although FOS (Fos proto-oncogene, AP-1 transcription factor subunit) has been
implicated in the regulation of cell proliferation and differentiation,
its differential roles in myogenic and adipogenic regulation remain
unclear. In this study, we revealed that FOS markedly
enhanced myogenic differentiation while inhibiting adipogenic differentiation
in muscle stem cells, indicating that it exerts distinct effects on
muscle development and intramuscular fat deposition. Mechanistically,
FOS modulated extracellular matrix signaling by regulating FAK and
PXN phosphorylation, acting as a molecular regulator between the muscle
and fat lineages. Furthermore, exon SNPs in FOS were
associated with slaughter weight and backfat thickness, and the mutant
genotypes weakened its antiadipogenic effect. Collectively, these
findings suggest that FOS is an important regulator
of myogenic and adipogenic differentiation and is a potential candidate
gene for the genetic improvement of meat quality traits.
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Lipids in Health and Disease
·
2026
·Vol. 25
·期 1
·116
·
IF 6.9
Wang Binqi,Zhang Ruikai,Wu Mengting,Cai Tiantian,Gao Chan,Wang Luping,Jin Taian,Xu Zhiyong,Jin Juan,He Qiang
Background Germacrone, a major bioactive component of Curcuma zedoaria , exhibits promising anticancer activity across various preclinical models. However, its molecular mechanisms in renal cell carcinoma (RCC), particularly regarding metabolic regulation, remain largely unexplored. This study aimed to investigate the therapeutic potential and underlying mechanisms of germacrone in RCC, specifically focusing on lipid metabolic reprogramming. Methods This study integrated network pharmacology and RNA sequencing transcriptomics to identify potential molecular targets of germacrone in 786-O and Caki-1 cells. In vivo antitumor efficacy was evaluated using the subcutaneous xenograft tumor model in BALB/c nude mice. In vitro, cell proliferation, apoptosis, migration, and cell cycle distribution were assessed using CCK-8, flow cytometry, transwell, and colony formation assays. To elucidate the underlying mechanism, de novo fatty acid synthesis was examined by quantifying intracellular triglyceride (TG) and total cholesterol (TC) levels. Interactions between germacrone and the c-Fos/SREBP1 signaling axis were analyzed using Western blot analysis, cellular thermal shift assays (CETSA), and molecular docking. Functional validation was performed using c-Fos overexpression plasmids to assess the extent to which germacrone’s effects were reversible. Results Germacrone significantly inhibited RCC growth in vivo, as evidenced by reduced tumor volume and weight, without detectable systemic toxicity. In vitro, germacrone suppressed proliferation, migration, and invasion in 786-O and Caki-1 cells, while promoting apoptosis and cell cycle arrest. Transcriptomic and molecular analyses indicated that germacrone targets the c-Fos transcription factor, leading to the downregulation of the SREBP1 signaling pathway and key lipogenic genes ( FASN and ACC1 ). This regulation resulted in a marked reduction in intracellular fatty acid and cholesterol biosynthesis. Notably, c-Fos overexpression significantly reversed the germacrone-induced suppression of lipid metabolism and cell viability, confirming that germacrone functions primarily by modulating the c-Fos/SREBP1 axis. Conclusion Germacrone serves as a novel modulator of the c-Fos/SREBP1 pathway, effectively inhibiting the growth of renal cancer by disrupting c-Fos-mediated lipid metabolism. These findings identify c-Fos as a potential therapeutic target and highlight germacrone as a promising candidate for RCC treatment strategies targeting metabolic reprogramming.
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高影响因子
Cell Death & Disease
·
2026
·
IF 12.2
Ao Liyan,Chen Zhiqiang,Zhang Jingliang,Wang Qi,Luo Jin,Li Zhuoran,Jiao Qilong,Ning Bobin,Peng Shiyuan,Hu Wenhao,Jia Yuqi,Ci Weimin,Wang Baojun,Dong Zhouhuan,Zhang Xu,Niu Shaoxi
Prostate cancer is a highly heterogeneous malignancy, with distinct subtypes displaying unique molecular and metabolic profiles. This study identifies a compensatory shift in α-ketoglutarate (α-KG) metabolism in prostate cancer, where the tumor relies on IDH1 to incorporate citrate into the TCA cycle. IDH1 inhibition, leads to lower α-KG levels. Since α-KG is required for HIF-1α hydroxylation, IDH1 inhibition stabilizes HIF-1α, which subsequently upregulates c-Fos. C-Fos enhances GLUD1 transcription, promoting the conversion of glutamate to α-KG as a compensatory mechanism. Additionally, c-Fos upregulates downstream effectors, including FOXC1 and SOX2, driving neuroendocrine differentiation in prostate cancer. Targeting α-KG-metabolizing enzymes, such as IDH1 or GLUD1, presents promising therapeutic strategies for prostate cancer subtypes by inhibiting tumor proliferation and inducing oxidative stress, thus sensitizing tumors to ferroptosis. Overall, these findings uncover a metabolic adaptation in response to IDH1 inhibition and highlight the pivotal role of c-Fos in mediating this compensatory pathway, offering new insights into potential metabolic targets for prostate cancer treatment and ferroptosis-based therapies.
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2023
·
IF 7.3
Leilei Pan,Shuifeng Xiao,Zichao Xu,Wenping Li,Long Zhao,Ling Zhang,Ruirui Qi,Junqin Wang,Yiling Cai
Background and Purpose We evaluated the hypothesis that central orexin application could counteract motion sickness responses through regulating neural activity in target brain areas. Experimental Approach Thec effects of intracerebroventricular (i.c.v.) injection of orexin-A and SB-334867 (OX 1 antagonist) on motion sickness-induced anorexia, nausea-like behaviour (conditioned gaping), hypoactivity and hypothermia were investigated in rats subjected to Ferris wheel-like rotation. Orexin-A responsive brain areas were identified using Fos immunolabelling and were verified via motion sickness responses after intranucleus injection of orexin-A, SB-334867 and TCS-OX2-29 (OX 2 antagonist). The efficacy of intranasal application of orexin-A versus scopolamine on motion sickness symptoms in cats was also investigated. Key Results Orexin-A (i.c.v.) dose-dependently attenuated motion sickness-related behavioural responses and hypothermia. Fos expression was inhibited in the ventral part of the dorsomedial hypothalamus (DMV) and the paraventricular nucleus (PVN), but was enhanced in the ventral part of the premammillary nucleus ventral part (PMV) by orexin-A (20 μg) in rotated animals. Motion sickness responses were differentially inhibited by orexin-A injection into the DMV (anorexia and hypoactivity), the PVN (conditioned gaping) and the PMV (hypothermia). SB-334867 and TCS-OX2-29 (i.c.v. and intranucleus injection) inhibited behavioural and thermal effects of orexin-A. Orexin-A (60 μg·kg −1 ) and scopolamine inhibited rotation-induced emesis and non-retching/vomiting symptoms, while orexin-A also attenuated anorexia with mild salivation in motion sickness cats. Conclusion and Implications Orexin-A might relieve motion sickness through acting on OX 1 and OX 2 receptors in various hypothalamus nuclei. Intranasal orexin-A could be a potential strategy against motion sickness.
研究领域:
神经科学
·
药理学
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PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 3
·
IF 7.7
Chao Li,Han Zhao,Jingjing Wang,Chenfei Liu,Shiqing He,Jingchao Zhou,Liangyu Li,Yiyao Liu,Qingping Wang,Xiaojing Shen,Junjie Wu,Guangquan Chen,Yu Wang,Liang Yang,Bin Du
Tumor-resident microbiota are identified as a critical modulator in the carcinogenesis and progression of cervical malignancies. However, the mechanisms linking these microbiota to cervical cancer remain poorly understood. In this study, we find that patients with cervical cancer exhibit increased microbiota diversity, characterized by eight distinct bacterial species that distinguish them from control subjects. Intratumoral or intravenous administration of an isolated strain, Gordonia polyisoprenivorans GP-2, derived from tumor-resident microbiota, significantly promotes the growth and metastasis of cervical cancer in mice. Further investigation reveals that GP-2 metabolizes host-derived choline to produce the bacterial metabolite lysophosphatidylcholine (lysoPC). We propose and validate the biosynthetic pathway for lysoPC in strain GP-2 and demonstrate that lysoPC activates the classical tumorigenic genes c-Jun / c-Fos using cervical tumor organoids derived from patients. These findings elucidate the mechanisms underlying microbiota-host crosstalk in cervical cancer and highlight a potential therapeutic target for intervening in tumor-resident bacteria.
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高影响因子
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