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2022 ◽  
Vol 12 ◽  
Author(s):  
Kaixuan Lv ◽  
Lingyu Kong ◽  
Mei Yang ◽  
Linlin Zhang ◽  
Shangmin Chu ◽  
...  

Atherosclerosis (AS) seriously impairs the health of human beings and is manifested initially as endothelial cells (ECs) impairment and dysfunction in vascular intima, which can be alleviated through mobilization of endothelial progenitor cells (EPCs) induced by stromal-cell-derived factor-1α (SDF-1α). A strong inverse correlation between HDL and AS has been proposed. The aim of the present work is to investigate whether 4F, an apolipoprotein A-I (apoA-I, major component protein of HDL) mimic peptide, can upregulate SDF-1α in mice and human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. The protein levels of SDF-1α were measured by ELISA assay. Protein levels of HIF-1α, phosphorylated Akt (p-Akt), and phosphorylated ERK (p-ERK) were evaluated by Western blotting analysis. The results show that L-4F significantly upregulates protein levels of HIF-1α, Akt, and ERK, which can be inhibited by the PI3K inhibitor, LY294002, or ERK inhibitor, PD98059, respectively. Particularly, LY294002 can downregulate the levels of p-ERK, while PD98059 cannot suppress that of p-Akt. D-4F can upregulate the levels of HIF, p-Akt, and p-ERK in the abdominal aorta and inferior vena cava from mice. These results suggest that 4F promotes SDF-1α expression in ECs through PI3K/Akt/ERK/HIF-1α signaling pathway.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Fengjie Liu ◽  
Meng Lan ◽  
Baoqi Ren ◽  
Lihong Li ◽  
Tengteng Zou ◽  
...  

Abstract Background Breast cancer is the most frequently occurring cancer among women. Baicalin has been shown to inhibit breast cancer proliferation, but poor aqueous solubility and unknown mechanism of action limit its application. This study aimed to investigate the antiproliferative effects of baicalin-loaded folic acid-modified albumin nanoparticles (FA-BSANPs/BA) in breast cancer MCF-7 cells and its relationship with autophagy and ROS-mediated p38 MAPK and Akt/mTOR signaling pathways. Cell viability was detected by MTT assay. Flow cytometry and fluorescence microscopy were used to detect cell cycle, apoptosis and autophagy. Western blot was used to detect protein expression. Results Compared with the control and free baicalin groups, FA-BSANPs/BA inhibited viability of MCF-7 cells and increased cells in S phase, apoptotic bodies, pro-apoptotic proteins, autophagy markers and autophagosomes. These effects could be reversed when combined with the autophagy inhibitor 3-methyladenine. FA-BSANPs/BA increased the levels of phosphorylated p38 MAPK, inhibited the levels of phosphorylated Akt and mTOR, and increased the level of ROS in MCF-7 cells. The effects of FA-BSANPs/BA could be reversed or enhanced using inhibitors of Akt, mTOR, p38 MAPK and ROS scavengers. Conclusions Encapsulation in folate albumin nanoparticles improved the antiproliferative activity of baicalin. FA-BSANPs/BA induced autophagy and apoptosis via ROS-mediated p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Yongsheng Huang ◽  
Sijia Liu ◽  
Mengjie Shan ◽  
Sophie C. Hagenaars ◽  
Wilma E. Mesker ◽  
...  

AbstractTransforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.


2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Han ◽  
Li Jiang ◽  
Xiaojie Song ◽  
Tianyi Li ◽  
Hengsheng Chen ◽  
...  

Neurogenesis and angiogenesis are widely recognized to occur during epileptogenesis and important in brain development. Because vascular endothelial growth factor (VEGF) is a critical neurovascular target in neurological diseases, its effect on neurogenesis, microvascular remodeling and epileptogenesis in the immature brain after lithium-pilocarpine-induced status epilepticus (SE) was investigated. The dynamic changes in and the correlation between hippocampal neurogenesis and microvascular remodeling after SE and the influence of VEGF or SU5416 injection into the lateral ventricles at different stages after SE on neurogenesis and microvascular remodeling through regulation of VEGF expression were assessed by immunofluorescence and immunohistochemistry. Western blot analysis revealed that the VEGFR2 signaling pathway promotes phosphorylated ERK and phosphorylated AKT expression. The effects of VEGF expression regulation at different stages after SE on pathological changes in hippocampal structure and spontaneous recurrent seizures (SRS) were evaluated by Nissl staining and electroencephalography (EEG). The results showed that hippocampal neurogenesis after SE is related to microvascular regeneration. VEGF promotion in the acute period and inhibition in the latent period after SE alleviates loss of hippocampal neuron, abnormal vascular regeneration and inhibits neural stem cells (NSCs) ectopic migration, which may effectively alleviate SRS severity. Interfering with VEGF via the AKT and ERK pathways in different phases after SE may be a promising strategy for treating and preventing epilepsy in children.


Author(s):  
Wei Zhu ◽  
Zhijie Xu ◽  
Meiyuan Huang ◽  
Xiang Wang ◽  
Xinxin Ren ◽  
...  

Ovarian cancer (OC) is typically diagnosed at an advanced stage and poses a significant challenge to treatment and recovery. Rencently, Adenosine deaminase RNA-specific B1 (ADARB1), an adenosine-to-inosine (A-to-I) RNA-editing enzyme, has been found to play an essential role in the development of cancer. However, the specific function of ADARB1 in ovarian cancer is still not fully understood. Here, we investigated the effects of ADARB1 on OC biology. By conducting bioinformatics analyses of several public databases, we found significantly decreased ADARB1 expression in OC cells and tissues. Moreover, RT-PCR and western blot showed lower ADARB1 expression in OVCAR3, HO8910pm and A2780 OC cells compared to human normal ovarian epithelial cell IOSE. Cell proliferation assay and clone formation assay showed that overexpression of ADARB1 (ADARB1-OE) inhibited the proliferation of tumor cells. Wound healing and transwell assay indicated that ADARB1-OE could suppress OC cell invasion and metastasis. Kaplan-Meier methods revealed that the patients with low level of ADARB1 displayed poor prognosis. TISIDB databases were further used to analyze the roles of ADARB1 in tumor-immune system interactions in OC patients. Furthermore, ADARB1-OE down-regulated the expression of phosphorylated AKT. Combination of ADARB1-OE and AKT inhibitor MK2206 exerted stronger cell growth inhibition. Thus, our investigation demonstrated that low levels of ADARB1 might be a potential target in the tumorigenesis and prognostic evaluation of OC patients.


2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Zhiqiang He ◽  
Shun Lei ◽  
Fucheng Liang ◽  
Liuchang Tan ◽  
Weinan Zhang ◽  
...  

Albendazole (ABZ) is an effective broad-spectrum anthelmintic agent that has been widely used for humans and animals. Previous studies have reported that ABZ exhibits antitumor effects against melanoma and other different cancer types; however, it is unknown whether ABZ exerts the inhibitory effect against melanoma metastasis. In this study, we aimed to investigate the inhibitory effect of ABZ on melanoma cells. Through in vitro studies, we discovered that low-dose ABZ treatment significantly inhibited the migration and invasion, but not the proliferation, of A375 and B16-F10 cells in a dose-dependent manner. Further analysis revealed that ABZ treatment reduced the expression level of snail family transcriptional repressor 1 (Snail) in the cytoplasm and nucleus by decreasing the levels of phosphorylated AKT (pAKT) Ser473/GSK-3β (pGSK-3β) Ser9 and increasing pGSK-3β/Tyr216, resulting in a significant upregulation of E-cadherin and downregulation of N-cadherin and ultimately reversing the epithelial-mesenchymal transition (EMT) process of melanoma cells. In contrast, the continuous activation of AKT via transfected plasmids elevated the protein levels of pAKT Ser473/pGSK-3β Ser9 and Snail and antagonized the inhibitory action of ABZ. We also confirmed that ABZ treatment effectively inhibited the lung metastasis of melanoma in nude mice in vivo. Subsequent immunohistochemical analysis verified the decreased pAKT Ser473/pGSK-3β Ser9 and increased pGSK-3β/Tyr216 levels in ABZ-treated subcutaneous tumors. Therefore, our findings demonstrate that ABZ treatment can suppress the EMT progress of melanoma by increasing the pGSK-3β/Tyr216-mediated degradation of Snail, which may be used as a potential treatment strategy for metastatic melanoma.


2021 ◽  
pp. 030089162110617
Author(s):  
Nerea Lago-Baameiro ◽  
Maria Santiago-Varela ◽  
Tamara Camino ◽  
Paula Silva-Rodríguez ◽  
Manuel Bande ◽  
...  

Introduction: PARK7/DJ-1 is an oncogene that is associated with tumorigenesis in many cancers. Recent studies have demonstrated the importance of DJ-1 in the origin and development of uveal melanoma (UM). We present an analysis of the role of the DJ-1 protein in UM cells, especially in its effect on proliferation and migration. Methods: UM cells from a primary tumor, Mel 270, and its liver metastasis, OMM2.5, were transfected with lentiviral-delivered shRNA against PARK7/DJ-1. Evaluation of cell migration and proliferation was performed using the xCELLigence real-time cell analyzer (RTCA). The effect of DJ-1 inhibition on the PTEN-Akt signaling pathway was also studied by immunoblotting. Results: The silencing of PARK7/DJ-1 oncoprotein expression produced a significant decrease of phosphorylated Akt (S473) in Mel270 and in metastatic OMM2.5 UM cells with no alteration on tumor suppressor PTEN expression. The diminution of PARK7/DJ-1 expression significantly inhibited real-time proliferation and invasion of Mel270 and OMM2.5 and the invasion potential of the metastatic cells. Conclusion: DJ-1 appears to play a key role on the PTEN/Akt pathway in UM. DJ-1 inhibition appears to have a negative effect on proliferation and invasion of UM cells. This suggests DJ-1 as a potential therapeutic target in UM.


Author(s):  
Nadya M. Morrow ◽  
Natasha A. Trzaskalski ◽  
Antonio A. Hanson ◽  
Evgenia Fadzeyeva ◽  
Dawn E. Telford ◽  
...  

Objective: Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout, and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT and FoxO1 (forkhead box O1) and normal Srebf1-c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by high-fat feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in high fat-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. Conclusions: Nobiletin opposed the effects of the high-fat diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.


2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Satoru Nihei ◽  
Junichi Asaka ◽  
Hiroaki Takahashi ◽  
Kenzo Kudo

Molecular mechanisms underlying the nephrotoxicity associated with bevacizumab are unclear. Endothelin-1 (ET-1) is involved in podocyte injury and proteinuria, and its level increases in most cases of kidney disorders. Forkhead box protein O1 (FoxO1), a transcription factor, is a major determinant of ET-1 promoter activation and is regulated by protein kinase B (Akt) phosphorylation-dependent nuclear exclusion. We evaluated the effect of bevacizumab on ET-1 production in human glomerular microvascular endothelial cells (hGECs). We analyzed the changes in the mRNA and protein levels of ET-1 in hGECs treated with bevacizumab using real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Changes in the protein levels and phosphorylation status of Akt and FoxO1 in hGECs treated with bevacizumab were analyzed by western blotting. After cell lysis, FoxO1 protein was isolated from the cytoplasmic and nuclear fractions. We also investigated the effects of AS1842856 (a FoxO1 inhibitor) on bevacizumab-induced ET-1 production. Bevacizumab significantly and dose-dependently increased the mRNA and protein levels of ET-1 in hGECs ( p  < 0.05). Bevacizumab treatment also led to a decrease in phosphorylated Akt protein levels. Inhibition of Akt activity by LY294002 promoted ET-1 production. Bevacizumab also induced an increase in FoxO1 protein levels in the nucleus. Inhibition of FoxO1 activity by AS1842856 resulted in decreased ET-1 levels in bevacizumab-treated hGECs. ET-1 axis activation, Akt inactivation, and FoxO1 nuclear localization are the molecular mechanisms underlying bevacizumab-induced nephrotoxicity. Therefore, inhibition of renal ET-1 production could be a promising approach to protect against or treat bevacizumab-induced nephrotoxicity.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Toshikazu Ito ◽  
Erquan Zhang ◽  
Ayaka Omori ◽  
Jane Kabwe ◽  
Masako Kawai ◽  
...  

Abstract Background Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats. Methods Fifty-one male Sprague–Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed. Results mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P < 0.05); 29.1 ± 1.5 mmHg (CH) (n = 10) vs. 17.5 ± 0.5 (control) (n = 10) (P < 0.05)], RV/LV + S [0.40 ± 0.01 (MCT) (n = 18) vs. 0.24 ± 0.01 (control) (n = 10) (P < 0.05); 0.41 ± 0.03 (CH) (n = 13) vs. 0.27 ± 0.06 (control) (n = 10) (P < 0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1 ± 1.1 mmHg (n = 11) (P < 0.05), RV/LV + S 0.30 ± 0.01 (n = 14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats. Conclusions We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.


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