INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Wenwei Li,Yang Liu,Ming Wei,Zhichao Yang,Hao Tang,Wei Huang
α-Solanine, a glycoalkaloid (GA) extracted from the stems of the potato plant, exhibits bioactivity and medicinal potential that necessitate further investigation. The impact and underlying mechanisms of α-Solanine on osteoarthritis (OA) remain to be elucidated. To achieve enhanced therapeutic outcomes, we have designed and synthesized a UIO-66-NH 2 @α-Solanine@PEI charged particle (USP) that amplifies the therapeutic effects of α-Solanine, demonstrating superior efficacy. Our approach involved the synthesis of a novel drug delivery system, the USP, to augment the therapeutic potential of α-Solanine in the treatment of OA. An OA rat model was established, and USP treatment was administered. The therapeutic effects were verified through histochemical staining and micro-CT. In vitro, α-Solanine significantly suppressed the expression of proteins related to glycolysis and notably inhibited ferroptosis. RNA sequencing revealed hypoxia-inducible factor-1α (HIF-1α) as a potential pathway mediating the effects of α-Solanine, and it was found that the co-addition of cycloheximide (CHX) led to a shortened decay time of HIF-1α. In vivo, rats with OA demonstrated significant inhibition of glycolysis and ferroptosis following treatment with USP, along with improvements in OA characteristics. These findings suggest that α-Solanine can inhibit the intense glycolysis associated with OA via the HIF-1α pathway and alleviate ferroptosis in chondrocytes. Treatment with USP demonstrated superior efficacy in the management of OA, providing a new therapeutic strategy for the disease.
研究领域:
医学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Xin Xie,Yan Zhu,Huimin Cheng,Haili Li,Yadi Zhang,Rong Wang,Wenyong Li,Fengrui Wu
Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo . The results showed that BPA (10 μM) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3 cells); moreover, it promoted ES-2 and OVCAR-3 cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5 μg/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2 cell in 10 μM BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRT‒PCR and western blotting results showed that BPA (10 μM) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1α and ERα in vitro/vivo ; whereas this effect was reduced after treatment with the ERα inhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERα with lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ERα/AKT/mTOR/HIF-1α signaling axis to enhance glycolysis.
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
CHEMICO-BIOLOGICAL INTERACTIONS
·
2025
·
IF 5.4
Lili Lu,Yuchen Ma,Qing Tao,Jing Xie,Xiao Liu,Yongkang Wu,Yang Zhang,Xiuli Xie,Mingming Liu,Yong Jin
Liver fibrosis is a passive and irreversible wound healing process caused by chronic liver injury. Research has shown that the upregulation of hypoxia inducible factor-1 alpha (HIF-1α) is closely related to the occurrence and development of liver fibrosis and HIF-1 α may be a promising target for the treatment of liver fibrosis. AMSP-30 m is a newly developed novel HIF-1α inhibitor by our group, which has strong anti-tumor and anti-inflammatory effects. In this study, we described the therapeutic effect and specific mechanism of AMSP-30 m on carbon tetrachloride (CCl 4 ) induced liver fibrosis in mice. Liver fibrosis induced by CCl 4 in mice and liver fibrosis induced by cobalt dichloride (CoCl 2 ) in LX-2 cells (human hepatic stellate cell (HSC) line) were studied. Hematoxylin & eosin (H&E)and Masson's trichrome staining were used to observe pathological conditions. Western Blot, immunofluorescence and immunohistochemistry were used to detect protein expression and localization in cells, and quantitative real-time PCR analysis (qRT-PCR) was used to detect mRNA expression. Biochemical detection kits were used to detect alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The results demonstrated that AMSP-30 m significantly alleviated pathological symptoms, reduced ALT and AST levels, and inhibited the expression of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1α1) in CCl 4 -induced liver fibrosis in mice. AMSP-30 m could significantly reduce the expression of HIF-1α and sonic hedgehog (Shh) pathway related proteins (Smoothened (Smo), Shh, and glioma-associated oncogene-1 (Gli-1)) in CCl 4 induced liver fibrosis mice. AMSP-30 m also played a similar role in the CoCl 2 -induced anoxic liver fibrosis model of LX-2 cells . Further experiments showed that Cyclopamine (a Shh inhibitor) could significantly inhibit the increase of α-SMA and COL1α1 resulting from HIF-1α but not significantly inhibit HIF-1α induced by CoCl 2 in LX-2 cells. And the combination of Cyclopamine and AMSP-30 m further reduced the expression of α-SMA and COL1α1 induced by HIF-1α. In summary, this study demonstrates that the HIF-1α inhibitor AMSP-30 m exerts a robust anti-fibrotic effect by inhibiting the Shh pathway, which is identified as a critical underlying mechanism. These findings suggest a promising therapeutic strategy for the treatment of liver fibrosis.
研究领域:
分子生物学
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药理学
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肝病学
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Li Wenchao,Chen SaiSai,Lu Jian,Mao Weipu,Zheng Shiya,Zhang Minhao,Wu Tiange,Chen Yurui,Lu Kai,Chu Chunyan,Shu Chuanjun,Hou Yue,Yang Xue,Shi Naipeng,Chen Zhijun,Zhang Lihua,Zhang Lei,Na Rong,Chen Ming,Ju Shenghong,Zhang Dingxiao,Ma Yi,Xu Bin
Immune checkpoint therapy for prostate cancer (PCa), a classic ‘immune-cold’ tumor characterized by an immunosuppressive tumor microenvironment, failed previously in clinical trials, but the underlying causes remain elusive. Here we find that YY1 + , immunosuppressive macrophages aggregate in the hypoxic areas of PCa. Mechanistically, hypoxia promotes the phase separation of YY1 in the nucleus, where YY1 binds to NUSAP1 and promotes the SUMOylation, phase separation and stabilization of HIF-1α. Either myeloid-specific conditional knockout of YY1 or a treatment with tenapanor for decreasing the YY1–NUSAP1–HIF-1α interaction impairs subcutaneous PCa tumor formation in mouse prostate tumor models. Lastly, a first-generation tetrahedral DNA nanostructure based on the proteolysis targeting chimera technique, termed YY1-DcTAC, allows targeting and degrading YY1 in tumor-associated macrophages for inducing antitumor effects and CD8 + T cell tumor infiltration in mouse tumor models. In summary, our findings underscore the pivotal role of YY1 in the hypoxia/HIF-1α pathway in tumor-associated macrophages and support the targeting of YY1 for treating PCa.
研究领域:
肿瘤生物学
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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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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
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2024
·Vol. 38
·期 11
·e23681
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IF 4.4
Shi-shi Liao,Le-le Zhang,Yi-guo Zhang,Jie Luo,Tulanisa Kadier,Ke Ding,Rong Chen,Qing-tao Meng
Ischemia–reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia–reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 μg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.
研究领域:
药理学
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病理生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jia Liu,Mengyu Li,Guobao Chen,Junhui Yang,Ying Jiang,Fang Li,Haibing Hua
Ethnopharmacological relevance Jianwei Xiaoyan Granule (JWXYG) is the traditional Chinese medicine preparation in Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, which has been widely used in clinical treatment of chronic atrophic gastritis (CAG). However, the material basis and potential mechanism of JWXYG in the treatment of CAG are not clear. Purpose To explore the material basis and potential mechanism of JWXYG in the treatment of CAG. Methods In this study, the components of JWXYG were analyzed by HPLC-Q-TOF-MS/MS. Then, the CAG model in rats established by a composite modeling method and MC cell model induced by MNNG were used to explore the improvement effect of JWXYG on CAG. Finally, the potential mechanism of JWXYG in the treatment of CAG was preliminarily predicted based on network pharmacology and validated experimentally. Results Thirty-one components of JWXYG were analyzed through HPLC-Q-TOF-MS/MS, such as albiflorin , paeoniflorin , lobetyolin firstly. Research results in vivo showed that the gastric mucosa became thinner, intestinal metaplasia appeared, the number of glands was reduced, the serum levels of PG I and PG II increased and the contents of G17 and IL-6 reduced in CAG model rats. After 4 weeks of JWXYG (2.70 g/kg) administration, these conditions were significantly improved. In addition, cell viability , migration, and invasion of MNNG-induced MC cells was inhibited by JWXYG treatment (800 μg/mL). Furthermore, the results of network pharmacology indicated that HIF-1 and VEGF signaling pathways might play important roles in the therapeutic process. Then the results of Western blot , immunohistochemistry and immunofluorescence confirmed that with JWXYG treatment, the increased expression of HIF-1α, VEGF and VEGFR2 in gastric issue of CAG rats were restrained. Eventually, potential components of JWXYG in the treatment of CAG were predicted through molecular docking to elucidate the material basis. Conclusion JWXYG could inhibit angiogenesis by regulating HIF-1α-VEGF pathway to exert therapeutic effects on CAG. Our study explored the potential mechanisms and material basis of JWXYG in the treatment of CAG and provides experimental data for the clinical rational application of JWXYG.
研究领域:
药理学
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中医中药
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2024
·Vol. 28
·期 20
·e70127
·
IF 4.3
Ming Zhang,Guan-Chun Dai,Yuan-Wei Zhang,Pan-Pan Lu,Hao Wang,Ying-Juan Li,Yun-Feng Rui
Diabetic calcific tendinopathy is the leading cause of chronic pain, mobility restriction, and tendon rupture in patients with diabetes. Tendon stem/progenitor cells (TSPCs) have been implicated in the development of diabetic calcified tendinopathy, but the molecular mechanisms remain unclear. This study found that diabetic tendons have a hyperoxic environment, characterized by increased oxygen delivery channels and carriers. In hyperoxic environment, TSPCs showed enhanced osteogenic differentiation and increased levels of reactive oxygen species (ROS). Additionally, hypoxia-inducible factor-1a (HIF-1a), a protein involved in regulating cellular responses to hyperoxia, was decreased in TSPCs by the ubiquitin-proteasome system. By intervening with antioxidant N-acetyl-L-cysteine (NAC) and overexpressing HIF-1a, we discovered that blocking the ROS/HIF-1a signalling axis significantly inhibited the osteogenic differentiation ability of TSPCs. Animal experiments further confirmed that hyperoxic environment could cause calcification in the Achilles tendon tissue of rats, while NAC intervention prevented calcification. These findings demonstrate that hyperoxia in diabetic tendons promotes osteogenic differentiation of TSPCs through the ROS/HIF-1a signalling axis. This study provides a new theoretical basis and research target for preventing and treating diabetic calcified tendinopathy.
研究领域:
糖尿病
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干细胞生物学
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细胞信号传导
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骨科
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2024
·Vol. 10
·期 1
·1-13
·
IF 6.1
Ruan Yuxia,Qiao Jianghua,Wang Jiabin,Liu Zhenzhen
Breast cancer (BC) poses a great threat to women’s health. Neuronal regeneration related protein (NREP) is a multifunctional protein that is involved in embryonic development, regeneration, and human disease. However, the biological function of NREP in tumors is rarely reported and its role in BC remains unknown. Bioinformatics analysis showed that NREP is highly expressed and closely correlated with poor survival in BC patients. Under hypoxic conditions, NREP was upregulated in BC cells, and this promotion was reversed by hypoxia-inducible factor HIF-1α suppression. Luciferase reporter system and chromatin immunoprecipitation assays confirmed that HIF-1α directly binds to the promoter of NREP to increase the transcriptional activity of NREP. NREP suppression inhibited cell proliferation, arrested the cell cycle at the G1/S phase, and promoted apoptosis and caspase-3 activity in BC cells. Suppression of NREP decreased the tube formation ability of HUVECs. In addition, NREP downregulation showed an inhibition effect on cell migration, invasion, and EMT of BC cells. In NREP overexpressed cells, all these changes were reversed. In vivo, animal experiments also confirmed that NREP promotes BC tumor growth and metastasis. In addition, NREP promoted cellular glycolysis and enhanced the levels of glucose consumption, ATP, lactate production, and glucose transporters expression in NREP-overexpressed BC cells. In summary, our results demonstrated that NREP could be transcriptional activated by HIF-1α, which may aggravate BC tumor growth and metastasis by promoting cellular glycolysis. This result suggested that NREP may play an essential part in BC progression.
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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癌症研究
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产品关联
DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2025
·
IF 5.1
Yanqiu Zhou,Junfang Shu,Yueying Zhao,Xiaorong Wu,Zhijun He,Xinzhe Lyu,Yong Zhou,Ling Ma
Background: Obesity is turning into a more critical problem for public health. Vitamin D3 (VD3) may be strongly linked to obesity.Objectives: The study aims to examine the influence of VD3 on IL-27 levels and the molecular mechanism by which VD3 affects white fat beige through the IL-27/P38MAPK/PGC-1α pathway.Methods: Firstly, a small sample population study was conducted to compare the disparities in serum 25(OH)D3 and IL-27 between individuals with obesity and healthy control groups. Secondly, twenty-four Wistar rats were separated into three groups: CON, HFD, and HFD + VD3 groups. Following 7 weeks of intervention, detection of biochemical indicators in serum by enzyme-linked immunosorbent assay (ELISA), mRNA, and protein expression of vitamin D receptor (VDR), IL-27R, P38MAPK, PGC-1α, and UCP-1 in inguinal adipose tissue by RT-qPCR and western blot. Finally, 3T3-L1 cells were induced into a hypertrophic adipose model, knock down IL-27 or PGC-1α using small interfering RNA, treated with 100 nM Calcitriol for 24 h, and divided into CON, PA, PA + 1,25(OH)2D3, PA + si IL-27, PA + si IL-27 + 1,25(OH)2D3, PA + si PGC-1α, and PA + si PGC-1α + 1,25(OH)2D3 groups. Detection of TC, TG, and IL-27 levels by ELISA, mRNA, and protein expression of VDR, IL-27R, P38MAPK, PGC-1α, UCP-1, and CD137 in cell supernatant by RT-qPCR and western blot.Results: A correlation was identified between serum 25(OH)D3 and IL-27 in the population-based study. However, no statistically significant difference in serum 25(OH)D3 or IL-27 levels was observed between the observation group and the control group. After VD3 intervention, TC, TG, and the number of LDs were significantly reduced in both HFD rats and 3T3-L1 cells, and serum IL-6 and MCP-1 in HFD rats were decreased. Meanwhile, there was a significant increase in mRNA and protein expression for VDR, IL-27R, P38MAPK, and PGC-1α. The expressions of the UCP-1 protein and the CD137 mRNA dramatically increased. Knockdown of IL-27 eliminated the increasing effect of calcitriol on the expression of P38MAPK, PGC-1α, UCP-1, and CD137 in 3T3-L1 cells, and knockdown of PGC-1α eliminated the increasing effect of calcitriol on the expression of UCP-1 and CD137 in 3T3-L1 cells.Conclusion: The study shows that VD3 may promote white fat beige through the IL-27/P38MAPK/PGC-1α pathway.
研究领域:
内分泌学
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分子生物学
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肥胖研究
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代谢紊乱
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产品关联
DOI
PubMed
高影响因子
EMBO REPORTS
·
2021
·Vol. 22
·期 3
·e50629
·
IF 8.807
Lei Liu,Yanjun Li,Jianing Wang,Di Zhang,Hao Wu,Wenhui Li,Huifang Wei,Na Ta,Yuyuan Fan,Yujiao Liu,Xiaohui Wang,Jun Wang,Xin Pan,Xudong Liao,Yushan Zhu,Quan Chen
Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.
研究领域:
细胞生物学
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分子生物学
·
代谢
✓ 已验证
DOI
PubMed
高影响因子
CURRENT PHARMACEUTICAL BIOTECHNOLOGY
·
2021
·Vol. 22
·期 5
·609-621
·
IF 2.837
Zheng Jing,Changyuan Wang,Shijie Wen,Yue Jin,Qiang Meng,Qi Liu,Jingjing Wu,Huijun Sun,Mozhen Liu
Background: Osteoporosis, characterized by bone loss, usually occurs with the increased bone resorption and decreased bone formation. H2O2-induced MC3T3-E1 cells are commonly used for the study of osteoblastic activities, which play a crucial role in bone formation. Objective: This study aimed to investigate the effects of Phosphocreatine (PCr) on the osteoblastic activities in H2O2-induced MC3T3-E1 cells and elaborate on the possible molecular mechanism. Methods: The Osteoprotegerin (OPG)/Receptor Activator of NF-ΚB Ligand (RANKL) ratio and osteogenic markers were detected to investigate the effects of PCr on osteoblastic activities, and the osteoblastic apoptosis was detected using Hochest staining. Moreover, oxidative stress, Adenosine Triphosphate (ATP) generation and the expression of Sirtuin 1 (SIRT1), Forkhead Box O 1 (FOXO1) and Peroxisome Proliferator-Activated Receptor Γ Coactivator-1α (PGC-1α) were also examined to uncover the possible molecular mechanism in H2O2-induced MC3T3-E1 cells. Result: The results showed that PCr promoted the osteoblastic differentiation by increasing the expression levels of osteogenic markers of Alkaline Phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as increased the OPG/RANKL ratio and suppressed the osteoblastic apoptosis in H2O2-induced MC3T3-E1 cells. Moreover, treatment with PCr suppressed reactive oxygen species (ROS) over-generation and promoted the ATP production as well as increased the PGC-1α, FOXO1 and SIRT1 protein expression levels in H2O2-induced MC3T3-E1 cells. Conclusion: PCr treatment could promote osteoblastic activities via suppressing oxidative stress and increasing the ATP generation in H2O2-induced MC3T3-E1 cells. In addition, the positive effects of PCr on osteoblasts might be regulated by SIRT1/FOXO1/ PGC-1α signaling pathway.
研究领域:
医学
·
分子生物学
✓ 已验证
DOI
高影响因子
CHEMISTRY & BIODIVERSITY
·
2024
·
IF 2.3
Hu-Ri Piao,Xin-Yu Ma,Ming-Yue Li,Kai-Han Jin,Zhen-Yuan Han,Yuan-Liang Gao,Yu-Qing Zhao,Xue-jun Jin
The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Here, three series of panaxadiol derivatives containing a thiazole moiety (5a-l, 7a-i, and 9a-i) were synthesized and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. Compounds 5d and 7b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 μM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50 µM. Molecular docking experiments were also performed to investigate the structure–activity relationship.
研究领域:
药理学
·
肿瘤学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
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