Aging-US
·
2024
·
IF 3.9
Yun Li,Meijuan Cheng,Jingjing Jin,Dongxue Zhang,Shenglei Zhang,Yaling Bai,Jinsheng Xu
Vascular calcification (VC) is directly related to high mortality in chronic kidney disease (CKD), and cellular apoptosis of vascular smooth muscle cells (VSMCs) is a crucial process in the initiation of VC. Microtubule affinity-regulating kinase 4 (Mark4), known as a serine/threonine protein kinase, can induce cell apoptosis and autophagy by modulating Akt phosphorylation. However, the potential functions and molecular mechanisms of Mark4 in VSMCs apoptosis and calcification need to be further explored. Initially, our data indicated that the mRNA expression of Mark4 was prominently elevated in high phosphorus-stimulated human VSMCs compared with the other members in Marks. Consistently, Mark4 expression was found to be significantly increased in the calcified arteries of both CKD patients and rats. In vitro , silencing Mark4 suppressed apoptosis-specific marker expression by promoting Akt phosphorylation, finally attenuating VSMCs calcification induced by high phosphate. Mechanically, the transcription factor Sp1 was enriched in the Mark4 promoter region and modulated Mark4 transcription. Moreover, SET domain-containing protein 8 (Setd8) was proved to interact with Sp1 and jointly participated in the transcriptional regulation of Mark4. Finally, rescue experiments revealed that Setd8 contributed to VSMCs apoptosis and calcification by modulating Mark4 expression. In conclusion, these findings reveal that Mark4 is transcriptionally activated by Sp1, which is interacted with Setd8, to promote VSMCs calcification through Akt-mediated antiapoptotic effects, suggesting that Mark4 represents a potent and promising therapeutic target for VC in CKD.
研究领域:
分子生物学
·
细胞生物学
·
心血管疾病
·
肾病学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Physiology
·
2018
·
IF 3.394
Deng Shuang,Zhou Jian-Lin,Fang Hong-Song,Nie Zhi-Gang,Chen Sen,Peng Hao
Glucocorticoids intake has become the most common pathogenic factor for osteonecrosis of the femoral head (ONFH). Annually, tens of millions of patients suffer from pain related to ONFH. Researchers have proposed several underlying mechanisms of ONFH, including osteocyte apoptosis, cell differentiation disorder, and angiogenesis hindrance. Sesamin, isolated from Sesamum indicum seeds, was reported could affect osteocyte inflammation and differentiation in osteoarthritis and osteoporosis. We investigated the underlying influence of sesamin on ONFH rat model. Fifteen male Sprague-Dawley rats were randomly divided into three groups. The ONFH model group only received the methylprednisolone (MPS) and lipopolysaccharide (LPS) injection to promote the development of ONFH. The sesamin treatment group was injected with sesamin, MPS, and LPS. The control group was untreated. Rats from above groups were sacrificed 4 weeks later. The effect of sesamin on ONFH rats was validated by H&E staining. TUNEL staining showed that femoral head necrosis was attenuated by sesamin. Furthermore, the phosphorylation of Akt was increased and the downstream cellular apoptosis signal pathway was inhibited. Intracellular ROS level was decreased after sesamin treatment. In conclusion, our findings suggest that sesamin protects the femoral head from osteonecrosis by inhibiting ROS-induced osteoblast apoptosis.
研究领域:
药理学
·
骨科
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Sun Chao-Yue,Cao Di,Ren Qian-Nan,Zhang Shan-Shan,Zhou Ning-Ning,Mai Shi-Juan,Feng Bing,Wang Hui-Yun
Aberrant activation of the Ras–ERK signaling pathway drives many important cancer phenotypes, and several inhibitors targeting such pathways are under investigation and/or approved by the FDA as single- or multi-agent therapy for patients with melanoma and non–small-cell lung cancer (NSCLC). Here, we show that betulinic acid (BA), a natural pentacyclic triterpenoid, inhibits cell proliferation, and induces apoptosis and protective autophagy in NSCLC cells. Thus, the cancer cell killing activity of BA is enhanced by autophagy inhibition. Mitogen-activated protein kinases, and especially ERK that facilitates cancer cell survival, are also activated by BA treatment. As such, in the presence of ERK inhibitors (ERKi), lung cancer cells are much more sensitive to BA. However, the dual treatment of BA and ERKi results in increased protective autophagy and AKT phosphorylation. Accordingly, inhibition of AKT has a highly synergistic anticancer effect with co-treatment of BA and ERKi. Notably, autophagy inhibition by hydroxychloroquine (HCQ) increases the response of lung cancer cells to BA in combination with ERKi. In vivo, the three-drug combination (BA, ERKi, and HCQ), resulted in superior therapeutic efficacy than single or dual treatments in the xenograft mouse model. Thus, our study provides a combined therapy strategy that is a highly effective treatment for patients with NSCLC.
研究领域:
肿瘤学
·
药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MedComm
·
2024
·Vol. 5
·期 12
·e70033
·
IF 10.7
Jing Li,Mimi Chen,Dingwen Huang,Ziyin Li,Yu Chen,Jinhua Huang,Yuanqun Chen,Zhili Zhou,Zhiying Yu
Ovarian cancer (OV) ranks among the deadliest gynecological cancer, known for its high risk of relapse and metastasis, and a general resistance to conventional platinum‐based chemotherapy. Selenoprotein I (SELENOI) is a crucial mediator implicated in human hereditary spastic paraplegia. However, its role in human tumors remains poorly elucidated. Here, we comprehensively analyzed SELENOI expression patterns, functions, and clinical implications across various malignancies through the integration of bulk transcriptomics, cancer databases, and in vitro and in vivo experiments. Pan‐cancer analysis indicated upregulated SELENOI expression across various cancers, correlating with augmented malignancy, suppressed tumor immunity and poor prognosis. Knockdown of SELENOI caused G0/G1‐phase cell cycle arrest and diminished aggressive cancer phenotypes in OV cells. Moreover, SELENOI inhibition augments ferroptosis and reverses the cisplatin resistance in OV cells by modulating Akt phosphorylation. Conversely, overexpression of SELENOI in OV cells enhanced therapeutic sensitivity to cisplatin by upregulating Akt phosphorylation. Importantly, in vivo studies demonstrated that SELENOI inhibition suppressed ovarian tumor growth and enhanced cisplatin's anticancer effects. These findings highlight the significant role of SELENOI in OV by modulating ferroptosis and chemotherapy resistance. Targeting SELENOI represents a promising therapeutic approach to promote the efficacy of platinum‐based chemotherapy in OV, particularly in cases of resistance. Graphic summary of targeting SELENOI for promoting ferroptosis and reversing chemoresistance in ovarian cancer. Inhibition of SELENOI activated unsaturated fatty acid synthesis and impaired Akt phosphorylation, resulting in the upregulation of ACSL4 expression and induction of ferroptosis. Reduced Akt phosphorylation also led to the downregulation of ALDH3A1 expression, a key gene associated with cisplatin‐resistance, thereby enhancing cisplatin cytotoxicity in SELENOI‐silenced ovarian cancer cells.
研究领域:
肿瘤学
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分子生物学
·
癌症治疗
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转化医学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2019
·Vol. 23
·期 3
·2174-2183
·
IF 4.658
Haiman Mu,Haiwen Liu,Jiayi Zhang,Jianhua Huang,Chen Zhu,Yue Lu,Yueping Shi,Yi Wang
In addition to the known antitumour effects of ursolic acid (UA), increasing evidence indicates that this molecule plays a role in cardiac protection. In this study, the effects of ursolic acid on the heart in mice treated with doxorubicin (DOX) were assessed. The results showed that ursolic acid improved left ventrical fractional shortening (LVFS) and left ventrical ejection fraction (LVEF) of the heart, increased nitrogen oxide (NO) levels, inhibited reactive oxygen species (ROS) production and decreased cardiac apoptosis in mice treated with doxorubicin. Mechanistically, ursolic acid increased AKT and endothelial nitric-oxide synthase (eNOS) phosphorylation levels, and enhanced eNOS expression, while inhibiting doxorubicin induced eNOS uncoupling through NADPH oxidase 4 (NOX4) down-regulation. These effects of ursolic acid resulted in heart protection from doxorubicin-induced injury. Therefore, ursolic acid may be considered a potential therapeutic agent for doxorubicin-associated cardiac toxicity in clinical practice.
研究领域:
药理学
·
心脏病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xinyi Zhao,Hua Su,Haiyan Chen,Xiusong Tang,Wenling Li,An Huang,Gang Fang,Qing Chen,Yudong Luo,Yuzhou Pang
Background Chronic liver injury (CLI) is a complex condition that requires effective therapeutic interventions. The Yi-Shan-Hong (YSH) formula is an empirically derived remedy that has shown effectiveness and safety in the management of chronic liver damage. However, the bioactive components and multifaceted mechanisms of YSH remain inadequately understood. Purpose To examine the bioactive compounds and functional processes that contribute to the therapeutic benefits of YSH against CLI. Methods Serum pharmacochemistry and network pharmacology were employed to identify active compounds and possible targets of YSH in CLI. In addition, YSH was also given in three doses to D -(+)-galactosamine hydrochloride ( D -GalN) -induced CLI rats to test its therapeutic efficacy. Results The analysis of serum samples successfully detected 25 compounds from YSH. Searches on the databases resulted in 277 genes as being correlated with chemicals in YSH, and 397 genes associated with CLI. In vivo experiments revealed that YSH displayed a notable therapeutic impact on liver injury caused by D -GalN. This was evidenced by enhanced liver function and histopathological improvements, reduced oxidative stress response, proinflammatory factors, and fibrosis levels. Importantly, no discernible adverse effects were observed. Furthermore, the administration of YSH treatment reversed the activation of AKT phosphorylation caused by D -GalN, aligning with the findings of the network pharmacology study. Conclusion These findings provide preclinical evidence of YSH's therapeutic value in CLI and highlight its hepatoprotective action via the PI3K/AKT signaling pathway.
研究领域:
药理学
·
药物化学
·
分子生物学
·
病理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Polymer Materials
·
2023
·
IF 5
Jingchen Gao,Xiyuran Wang,Xiangyi Kong,Xujin Yao,Jinyang Ren,Shujun Chen,Na Shen,Zhuo Li,Yitian Wang,Ye Wei,Oleg Glebov,Fengyuan Che,Qi Wan
Proline, a nonessential amino acid, has been demonstrated to possess neuroprotective capabilities in the central nervous system (CNS). However, the mechanisms through which it impacts cerebral ischemia–reperfusion (I/R) injuries remain unclear. Our study observed a decrease in proline concentrations within the ischemic brain tissues of I/R mice. Supplementing proline protected against ischemic neuronal death, both in vivo and in vitro, suggesting its potential as a neuroprotectant. However, our data indicated that proline has a low permeability to the blood–brain barrier (BBB) in mice. Therefore, it is clinically infeasible to develop proline as a stroke therapy. To develop an approach to deliver proline into the injured brain, we engineered a method to transport proline to the injured brain. We prepared chitosan nanoparticles (NPs) loaded with proline utilizing the ion cross-linking method. Our findings demonstrated that the proline-loaded chitosan NPs efficiently passed through the BBB and delivered proline into the injured brain, thereby conferring neuroprotection. Further exploration revealed that proline upregulated the level of annexin A6 (ANX6)/β1 integrin, which, in turn, increased the phosphorylation of cell-survival-promoting kinase Akt. This sequence of events consequently promotes neuronal survival following I/R. In conclusion, our study has developed a neuroprotection approach by which low-BBB-permeable proline is delivered by chitosan NPs into the brain. Furthermore, this study suggests that the neuroprotective role of proline in I/R is mediated by the ANX6/β1 integrin/Akt signaling pathway.
研究领域:
神经科学
·
药学
·
分子生物学
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产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Mengqi Jia,Ruilin Lu,Caikun Liu,Xiaodong Zhou,Pengfei Li,Shiyong Zhang
Surgical excision is the main treatment for skin cancer, but the tumor recurrence caused by the “vicious cycle” between residual tumor cells and postoperative inflammation remains a challenge. Herein, a new material, which can break the “vicious cycle”, was developed by incorporating chitosan oligosaccharides into lipoic acid hydrogel (COS@LA-hydrogel). When implanted at the resection site, the COS@LA-hydrogel would have a sustained release of LA and COS, which could not only kill residual tumor cells by synergistically reducing AKT phosphorylation but also decrease inflammation by inhibiting the expression of tumor necrosis factor-α (TNF-α) and inhibiting bacterial infection, respectively. As a proof of concept, in the postoperative melanoma resection model, the COS@LA-hydrogel reduced the expression of pro-inflammatory factors TNF-α and interleukin-6 (IL-6) by up to 78 and 80%, respectively, and they showed almost no tumors and the median survival of the mice was 2.5 times longer than that of the control group. The hydrogel with the function of “vicious cycle” breaking holds clinical potential.
研究领域:
材料科学
·
癌症研究
·
生物医学工程
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Yang Siwen,Qu Yunhe,Chen Jiyu,Chen Si,Sun Lin,Zhou Yifa,Fan Yuying
Insufficient pancreatic β-cell or insulin-producing β-cell are implicated in all types of diabetes mellitus. Our previous studies showed bee pollen polysaccharide RBPP-P improves insulin resistance in type 2 diabetic mice by inhibiting liver fat deposition. However, its potential of regulating β-cell function and integrity is not fully known. Herein, we observed that β-cell proliferation (n = 10), insulin synthesis (n = 5, p = 0.01684) and insulin incretion (n = 5, p = 0.02115) were intensely activated in MIN6 cells when treatment with RBPP-P. In alloxan-induced diabetic mice, oral administration of RBPP-P (n = 10) effectively decreased the blood glucose (p = 0.0326), drink intake (p < 0.001) and urine (p < 0.001). It directly stimulated phosphorylation of p38 (p = 0.00439), ERK (p = 0.02951) and AKT (p = 0.0072) to maintain the islet function and mass. Thus, our data suggest that RBPP-P is a natural compound to regulate β-cell proliferation and function, indicating it might have therapeutic potential against type 1 diabetes.
研究领域:
药理学
·
内分泌学
·
糖尿病研究
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2024
·
IF 3.3
Li Guan,Yanxin Xia,Pengfei Song,Huiru Zhao,Shengjie Zhang,Wanzhen Su,Aiyun Li,Weize Li
In this paper, we investigated the anticancer effect and the mechanism of our newly synthesized bibenzyl 8Ae against human lung cancer A549 cells. Compound 8Ae could induce apoptosis by inhibiting the glycolysis in A549 cells. Hexokinase 2 (HK2), the first key enzyme in glycolysis process, was significantly down-regulated by 8Ae. Besides, compound 8Ae induced HK2 dissociated from mitochondria to cytosol, which could be induced by inhibiting the phosphorylation of Akt. In addition, 8Ae could induce mitochondrial-mediated apoptosis, and mitochondrial membrane potential (MMP) was decreased. After 8Ae treatment, the Bax/Bcl-2 ratio was increased and cytochrome c (Cyt c ) was release from mitochondria to cytosol. Molecular docking indicated that 8Ae have an interaction with HK2 by extending into acitve pockets of the protein to form stable hydrogen bonds. Additionally, 8Ae had significantly improved pharmacokinetic properties through the prediction, comparison, and analysis of the ADMET properties of 8Ae and moscatilin (MST). Taken together, 8Ae might inhibit glycolysis by stimulating the shedding of HK2 from mitochondria and promoting mitochondria-regulated apoptosis to inhibit the proliferation of A549 cells. This article provides a research basis for bibenzyl compounds as new small molecule drugs for lung cancer.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2017
·
IF 4.581
Xiaojiao Ren,Xiaojian Fu,Xinhua Zhang,Shiqiang Chen,Shuguang Huang,Lun Yao,Guoquan Liu
Low testosterone levels are strongly related to obesity in males. The balance between the classically M1 and alternatively M2 polarized macrophages also plays a critical role in obesity. It is not clear whether testosterone regulates macrophage polarization and then affects adipocyte differentiation. In this report, we demonstrate that testosterone strengthens interleukin (IL) -4-induced M2 polarization and inhibits lipopolysaccharide (LPS)-induced M1 polarization, but has no direct effect on adipocyte differentiation. Cellular signaling studies indicate that testosterone regulates macrophage polarization through the inhibitory regulative G-protein (Gαi) mainly, rather than via androgen receptors , and phosphorylation of Akt. Moreover, testosterone inhibits pre-adipocyte differentiation induced by M1 macrophage medium. Lowering of serum testosterone in mice by injecting a luteinizing hormone receptor (LHR) peptide increases epididymal white adipose tissue. Testosterone supplementation reverses this effect. Therefore, our findings indicate that testosterone inhibits pre-adipocyte differentiation by switching macrophages to M2 polarization through the Gαi and Akt signaling pathways.
研究领域:
内分泌学
·
免疫学
·
细胞生物学
·
肥胖研究
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zuo Wanyun,Liu Na,Zeng Yunhong,Xiao Zhenghui,Wu Keke,Yang Fan,Li Biao,Song Qingqing,Xiao Yunbin,Liu Qiming
Luteolin is a flavonoid compound with a variety of pharmacological effects. In this study, we explored the effects of luteolin on monocrotaline (MCT) induced rat pulmonary arterial hypertension (PAH) and underlying mechanisms. A rat PAH model was generated through MCT injection. In this model, luteolin improved pulmonary vascular remodeling and right ventricular hypertrophy, meanwhile, luteolin could inhibit the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent manner. Moreover, our results showed that luteolin could downregulate the expression of LATS1 and YAP, decrease YAP nuclear localization, reduce the expression of PI3K, and thereby restrain the phosphorylation of AKT induced by PDGF-BB. In conclusion, luteolin ameliorated experimental PAH, which was at least partly mediated through suppressing HIPPO-YAP/PI3K/AKT signaling pathway. Therefore, luteolin might become a promising candidate for treatment of PAH.
研究领域:
药理学
·
心血管疾病
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）