scholarly journals Expression Pattern and Regulatory Role of microRNA-23a in Conjugated Linoleic Acids-Induced Apoptosis of Adipocytes

2016 ◽  
Vol 40 (3-4) ◽  
pp. 668-680 ◽  
Author(s):  
Renli Qi ◽  
Qi Wang ◽  
Jing Wang ◽  
Jinxiu Huang ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Critical Role ◽  
Fat Cells ◽  
Conjugated Linoleic Acids ◽  
Cellular Mechanisms ◽  
Over Expression ◽  
Functional Studies ◽  
Induced Apoptosis

Background/Aims: Conjugated linoleic acids (CLAs) are known to induce apoptosis in adipocytes; however, the cellular mechanisms involved remained illdefined. We explored the different apoptotic induction effects of two CLA isomers on adipocytes and then investigated the expression and function of microRNAs (miRNAs) related to the apoptosis. Methods: TUNEL and FCM assays were used to detect CLAs-induced adipocyte apoptosis. Microarrays were used to compare the differential expression of miRNAs. MiR-23a, a miRNA that showed significant changes in expression in the CLA-treated cells, was selected for the subsequent functional studies via over-expression and knock down in in vivo and in vitro experiments. Results: C9, t11-CLA exhibited a stronger induction of apoptosis in the differentiated 3T3-L1 adipocytes than t10, c12-CLA. However, t10, c12-CLA could rapidly activate NF-κB, which may have caused their different apoptotic effects. MiR-23a was markedly down-regulated by the CLAs treatment and miR-23a over-expression attenuated CLA-induced apoptosis. Apoptosis protease-activating factor 1 (APAF1) was identified as a target gene of miR-23a. In an in vivo experiment endogenous miR-23a was down-regulated in mice fed with a mixture of both CLAs. The mice also exhibited less fat deposition and more apoptotic fat cells in adipose tissue. Moreover, endogenous miR-23a was suppressed in mice via intravenous injection with an antagomir which resulted in decreased body weight, increased number of apoptotic fat cells and increased APAF1 expression in adipose tissue. Conclusion: Taken together, our results suggest that miR-23a plays a critical role in CLA-induced apoptosis in adipocytes via controlling APAF1 expression.

scholarly journals Cellular adaptations in fat tissue of exercise-trained miniature swine: role of excess energy intake

2000 ◽  
Vol 88 (3) ◽  
pp. 881-887 ◽  
Author(s):  
Gale B. Carey
Keyword(s):  
Adipose Tissue ◽  
Energy Intake ◽  
Excess Energy ◽  
Fat Tissue ◽  
Cellular Mechanisms ◽  
Miniature Swine ◽  
Extracellular Adenosine

This study examined the influence of energy expenditure and energy intake on cellular mechanisms regulating adipose tissue metabolism. 1 Twenty-four swine were assigned to restricted-fed sedentary, restricted-fed exercise-trained, full-fed sedentary, or full-fed exercise-trained groups. After 3 mo of treatment, adipocytes were isolated and adipocyte size, adenosine A1 receptor characteristics, and lipolytic sensitivity were measured. Swine were infused with epinephrine during which adipose tissue extracellular adenosine, plasma fatty acids, and plasma glycerol were measured. Results revealed that adipocytes isolated from restricted-fed exercised swine had a smaller diameter, a lower number of A1 receptors, and a greater sensitivity to lipolytic stimulation, compared with adipocytes from full-fed exercised swine. Extracellular adenosine levels were transiently increased on infusion of epinephrine in adipose tissue of restricted-fed exercised but not full-fed exercised swine. These results suggest a role for adenosine in explaining the discrepancy between in vitro and in vivo lipolysis findings and underscore the notion that excess energy intake dampens the lipolytic sensitivity of adipocytes to β-agonists and adenosine, even if accompanied by exercise training.

scholarly journals ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chuangyu Wen ◽  
Huihui Wang ◽  
Xiaobin Wu ◽  
Lu He ◽  
Qian Zhou ◽  
...  
Keyword(s):  
Critical Role ◽  
Thioredoxin Reductase ◽  
Akt Pathway ◽  
Ros Generation ◽  
In Vivo Models ◽  
M Phase ◽  
Tumorigenesis And Progression ◽  
Induced Apoptosis

Abstract Novel drugs are urgently needed for gastric cancer (GC) treatment. The thioredoxin-thioredoxin reductase (TRX-TRXR) system has been found to play a critical role in GC tumorigenesis and progression. Thus, agents that target the TRX-TRXR system may be highly efficacious as GC treatments. In this study, we showed that chaetocin, a natural product isolated from the Chaetomium species of fungi, inhibited proliferation, induced G2/M phase arrest and caspase-dependent apoptosis in both in vitro and in vivo models (cell xenografts and patient-derived xenografts) of GC. Chaetocin inactivated TRXR-1, resulting in the accumulation of reactive oxygen species (ROS) in GC cells; overexpression of TRX-1 as well as cotreatment of GC cells with the ROS scavenger N-acetyl-L-cysteine attenuated chaetocin-induced apoptosis; chaetocin-induced apoptosis was significantly increased when GC cells were cotreated with auranofin. Moreover, chaetocin was shown to inactivate the PI3K/AKT pathway by inducing ROS generation; AKT-1 overexpression also attenuated chaetocin-induced apoptosis. Taken together, these results reveal that chaetocin induces the excessive accumulation of ROS via inhibition of TRXR-1. This is followed by PI3K/AKT pathway inactivation, which ultimately inhibits proliferation and induces caspase-dependent apoptosis in GC cells. Chaetocin therefore may be a potential agent for GC treatment.

Regulation of lipolysis by somatotropin: functional alteration of adrenergic and adenosine signaling in bovine adipose tissue

1997 ◽  
Vol 152 (3) ◽  
pp. 465-475 ◽  
Author(s):  
K L Houseknecht ◽  
D E Bauman
Keyword(s):  
Adipose Tissue ◽  
Signaling Proteins ◽  
Heterotrimeric G Proteins ◽  
Adrenergic Stimulation ◽  
Cellular Mechanisms ◽  
Lactating Cows ◽  
Adipose Tissue Lipolysis ◽  
Stimulation Of

To investigate the cellular mechanisms of somatotropin (ST) action on adipose tissue lipolysis, experiments were conducted using adipose tissue taken from lactating cows treated with excipient or ST (40 mg/day). Stimulation of lipolysis in vitro by the effectors isoproterenol with or without adenosine deaminase, dibutyryl cAMP with or without isobutylmethylxanthine, and forskolin was not altered by ST treatment. Conversely, the response to the antilipolytic effector, phenylisopropyladenosine (PIA), was significantly reduced in adipose tissue explants from ST or fasted cows. The different responses to adrenergic-stimulating agents (in vivo) and PIA (in vitro) were not due to differences in the abundance of α, β or γ subunits of the stimulatory (Gs) and inhibitory (Gi) subunits of the heterotrimeric G-proteins which bind to the β-adrenergic and adenosine receptors respectively. However, the functionality of Gi proteins, as assessed by their ability to be ADP-ribosylated by pertussis toxin, was significantly reduced in ST-treated but not fasted cows. These data highlight differential regulation of signaling proteins by ST and fasting, both of which result in enhanced in vivo response to adrenergic stimulation of lipolysis. Journal of Endocrinology (1997) 152, 465–475

scholarly journals The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

2020 ◽  
Author(s):  
Marine Lanfranchi ◽  
Géraldine Meyer-Dilhet ◽  
Raphael Dos Reis ◽  
Audrey Garcia ◽  
Camille Blondet ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Metabolic Regulation ◽  
Critical Role ◽  
Dual Function ◽  
Axon Branching ◽  
Cellular Mechanisms ◽  
Peripheral Neurons ◽  
Branch Formation

ABSTRACTThe precise regulation of the cellular mechanisms underlying axonal morphogenesis is essential to the formation of functional neuronal networks. We previously identified the autism-candidate kinase NUAK1 as a central regulator of axon branching in mouse cortical neurons through the control of mitochondria trafficking. How does local mitochondrial position or function regulate axon branching during development? Here, we characterized the metabolic regulation in the developing axon and report a marked metabolic decorrelation between axon elongation and collateral branching. We next solved the cascade of event leading to presynaptic clustering and mitochondria recruitment during spontaneous branch formation. Interestingly and contrary to peripheral neurons, mitochondria are recruited after but not prior to branch formation in cortical neurons. Using flux metabolomics and fluorescent biosensors, we observed that NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration. Upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Altogether, our results indicate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondria distribution and activity, and suggest that a mitochondrial-dependent remodeling of local metabolic homeostasis plays a critical role during axon morphogenesis.

scholarly journals LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function

2019 ◽  
Vol 28 (16) ◽  
pp. 2696-2710 ◽  
Author(s):  
Rebecca Wallings ◽  
Natalie Connor-Robson ◽  
Richard Wade-Martins
Keyword(s):  
Critical Role ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Mechanisms ◽  
Genomic Locus ◽  
Lysosomal Dysfunction ◽  
Lrrk2 G2019s ◽  
Lrrk2 Kinase

Abstract Lysosomal dysfunction lies at the centre of the cellular mechanisms underlying Parkinson’s disease although the precise underlying mechanisms remain unknown. We investigated the role of leucine-rich repeat kinase 2 (LRRK2) on lysosome biology and the autophagy pathway in primary neurons expressing the human LRRK2-G2019S or LRKK2-R1441C mutant or the human wild-type (hWT-LRRK2) genomic locus. The expression of LRRK2-G2019S or hWT-LRRK2 inhibited autophagosome production, whereas LRRK2-R1441C induced a decrease in autophagosome/lysosome fusion and increased lysosomal pH. In vivo data from the cortex and substantia nigra pars compacta of aged LRRK2 transgenic animals revealed alterations in autophagosome puncta number reflecting those phenotypes seen in vitro. Using the two selective and potent LRRK2 kinase inhibitors, MLi-2 and PF-06447475, we demonstrated that the LRRK2-R1441C-mediated decrease in autolysosome maturation is not dependent on LRRK2 kinase activity. We showed that hWT-LRRK2 and LRRK2-G2019S bind to the a1 subunit of vATPase, which is abolished by the LRRK2-R1441C mutation, leading to a decrease in a1 protein and cellular mislocalization. Modulation of lysosomal zinc increased vATPase a1 protein levels and rescued the LRRK2-R1441C-mediated cellular phenotypes. Our work defines a novel interaction between the LRRK2 protein and the vATPase a1 subunit and demonstrates a mode of action by which drugs may rescue lysosomal dysfunction. These results demonstrate the importance of LRRK2 in lysosomal biology, as well as the critical role of the lysosome in PD.

scholarly journals Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3441-3450 ◽  
Author(s):  
Guang-Biao Zhou ◽  
Hui Kang ◽  
Lan Wang ◽  
Li Gao ◽  
Ping Liu ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Target Genes ◽  
Critical Role ◽  
Ectopic Expression ◽  
Medicinal Herbs ◽  
Leukemic Cells ◽  
Apoptotic Effect ◽  
Induced Apoptosis

Abstract Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.

scholarly journals Fatostatin reverses progesterone resistance by inhibiting the SREBP1-NF-κB pathway in endometrial carcinoma

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Xiaohong Ma ◽  
Tianyi Zhao ◽  
Hong Yan ◽  
Kui Guo ◽  
Zhiming Liu ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Recurrent Cancer ◽  
Over Expression ◽  
Functional Studies ◽  
Progesterone Resistance

AbstractProgesterone resistance can significantly restrict the efficacy of conservative treatment for patients with endometrial cancer who wish to preserve their fertility or those who suffer from advanced and recurrent cancer. SREBP1 is known to be involved in the occurrence and progression of endometrial cancer, although the precise mechanism involved remains unclear. In the present study, we carried out microarray analysis in progesterone-sensitive and progesterone-resistant cell lines and demonstrated that SREBP1 is related to progesterone resistance. Furthermore, we verified that SREBP1 is over-expressed in both drug-resistant tissues and cells. Functional studies further demonstrated that the inhibition of SREBP1 restored the sensitivity of endometrial cancer to progesterone both in vitro and in vivo, and that the over-expression of SREBP1 promoted resistance to progesterone. With regards to the mechanism involved, we found that SREBP1 promoted the proliferation of endometrial cancer cells and inhibited their apoptosis by activating the NF-κB pathway. To solve the problem of clinical application, we found that Fatostatin, an inhibitor of SREBP1, could increase the sensitivity of endometrial cancer to progesterone and reverse progesterone resistance by inhibiting SREBP1 both in vitro and in vivo. Our results highlight the important role of SREBP1 in progesterone resistance and suggest that the use of Fatostatin to target SREBP1 may represent a new method to solve progesterone resistance in patients with endometrial cancer.

scholarly journals hPER3 promotes adipogenesis via hHSP90AA1-mediated inhibition of Notch1 pathway

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Xinxing Wan ◽  
Liyong Zhu ◽  
Liling Zhao ◽  
Lin Peng ◽  
Jing Xiong ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Stromal Cells ◽  
Critical Role ◽  
Human Adipose Tissue ◽  
Positive Role ◽  
Positive Regulator ◽  
Adipose Derived Stromal Cells

AbstractThe period circadian regulator 3 (PER3) has been reported to play a negative role in human immortalized bone marrow-derived Scp-1 cells (iBMSCs) and patient adipose-derived stromal cells (PASCs) or a negative/positive role in mice adipogenesis. However, human PER3 (hPER3) was identified as a positive regulator of human adipose tissue-derived stromal cells (hADSCs) adipogenesis in this study. Silencing or overexpression of hPER3 in hADSCs inhibited and promoted adipogenesis in vitro. In vivo, the overexpression of hPER3 increased high-fat diet-induced inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) forms, increasing systemic glucose intolerance and insulin resistance. Molecularly, hPER3 does not interact with hPPARγ, but represses Notch1 signaling pathway to enhance adipogenesis by interacting with hHSP90AA1, which is able to combine with the promoter of hNotch1 and inactivate its expression. Thus, our study revealed hPER3 as a critical positive regulator of hADSCs adipogenesis, which was different from the other types of cells, providing a critical role of it in treating obesity.

scholarly journals NPR3 inhibits EMT and Tumour Metastasis of Human Osteosarcoma by Activating AKT/mTOR-mediated Autophagy

2021 ◽  
Author(s):  
Zhihong Yao ◽  
Yihao Yang ◽  
Jiaxiang Chen ◽  
Ting Chen ◽  
Lei Han ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Loss Of Function ◽  
Over Expression ◽  
Functional Studies ◽  
Qrt Pcr ◽  
Tumour Metastasis ◽  
Lower Expression

Abstract BackgroundOsteosarcoma is an aggressive primary malignant cancer of bone mainly occurring in adolescence with a characteristic of high metastasis and relapse rate. In our previous study, we first identified that NPR3 was significantly decreased in OS samples. Here, we purposed to investigate the effect and the possible mechanisms of NPR3 on the progression of human OS. MethodsThe expression of NPR3 in OS patients and cells was detected by qRT-PCR, and IHC analysis. The effect of the expression of NPR3 on tumour metastasis was examined in vitro and in vivo. The molecular mechanisms of the regulation of NPR3 were evaluated in vitro and in vivo. The clinical relevance of 5-year overall survival with the expression of NPR3 was evaluated in 294 patients with OS. ResultsFirstly, we indicated that NPR3 was substantially downregulated expression in OS tissues and cells by qRT-PCR and IHC assay. And the patients with lower expression of NPR3 have a poor prognosis. Functional studies revealed that over-expression of NPR3 inhibited the proliferation and invasion of cells. Meanwhile, over-expression of NPR3 markedly inhibited tumorigenesis and weakened tumour metastasis in vivo. Interestingly, we found that over-expression of NPR3 could induce autophagy, promote apoptosis and inhibit EMT. Additionally, overexpression of NPR3 decreased the phosphorylation levels of AKT and mTOR. Loss-of-function experiments displayed that effects of NPR3 were weakened by treatment with the specific autophagy inhibitor Baf-A1 and CQ. ConclusionsTaken together, these results demonstrated that down-regulation of NPR3 promote lung metastasis of human OS by promoting EMT in part through the AKT/mTOR mediated autophagy, suggesting that NPR3 has therapeutic potential for OS patients with metastasis.

scholarly journals Effect of miR-21 on Apoptosis in Lung Cancer Cell Through Inhibiting the PI3K/ Akt/NF-κB Signaling Pathway in Vitro and in Vivo

2018 ◽  
Vol 46 (3) ◽  
pp. 999-1008 ◽  
Author(s):  
Bing Zhou ◽  
Dimin Wang ◽  
Gaozhong Sun ◽  
Fuyang Mei ◽  
Yong Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathway ◽  
Small Cell Lung Carcinoma ◽  
Critical Role ◽  
Migration And Invasion ◽  
Tunel Staining ◽  
Cell Lung Carcinoma ◽  
Induced Apoptosis

Background/Aims: Lung cancer is one of the most common malignancies in the world. Apoptosis-stimulating protein of p53 (ASPP2), a tumorigenesis related protein, plays a critical role in the initiation and development of various types of cancers. However, the effect of ASPP2 on lung cancer remains unknown. The purpose of this study aims to investigate the mechanism of ASPP2 regulated by miR-21 in lung cancer in vitro and in vivo. Methods: In the study, migration and invasion assays, apoptosis assay, caspase activity assay, TUNEL staining, real time PCR and western blot were used to investigate the mechanism of ASPP2 regulated by miR-21 in lung cancer in vitro and in vivo. Results: We demonstrated that the miR-21 inhibitor induced apoptosis through inhibiting the PI3K/Akt/NF-κB signaling pathway in non-small cell lung carcinoma (NSCLC). Moreover, ASPP2 was directly targeted by miR-21 in NSCLC cells. Down-regulation of miR-21 suppressed cell migration and invasion, as well as the EMT signaling pathway in NSCLC cells. Furthermore, the miR-21 inhibitor induced cell apoptosis via the caspase dependent pathway in NSCLC cells. The miR-21 inhibitor enhanced caspase-3, 8, 9 activity in NSCLC cells. In addition, the caspase inhibitor significantly reduced the apoptosis induced by the miR-21 inhibitor in NSCLC cells. Conclusions: Our results revealed that the miR-21 inhibitor could induce apoptosis through inhibiting the PI3K/Akt/NF-κB signaling pathway in human NSCLC cells, and might serve as a therapeutic strategy to treat NSCLC.

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