The polyphenol/saponin-rich Rhus tripartita extract has an apoptotic effect on THP-1 cells through the PI3K/AKT/mTOR signaling pathway

Abstract Background Hyperactivation of mechanistic target of rapamycin (mTOR) signaling pathway is involved in the regulation of cellular growth, proliferation, and more in general, is a common phenomenon in most types of cancers. Thus, natural substances targeting this pathway can be of great therapeutic potential in supporting the treatment of tumor patients. Rhus tripartita (Ucria) Grande is a plant growing in desertic areas which is traditionally used for the treatment of several diseases in Tunisia. In the present work, the biochemical profile of the main compounds present in the plant leaf extract was determined and the anti-leukemic potential of the plant extracts against acute monocytic leukaemia (AML) THP-1 cells was investigated. Methods After HPLC identification of some phenolic compounds present in the plant extract and the quantification of saponin content, the cytotoxic effect of Rhus tripartita extracts on THP-1 cell culture was evaluated using the colorimetric MTT assay for cell viability. THP-1 cells were incubated with medium containing the relative IC50 concentrations of total plant extract, saponin extract and some standard compounds (rutin (R); kaempferol (K); mixture of catechin, epicatechin, and epicatechin-gallate (CEEG); ellagic acid (EA). Finally, qRT-PCR and western blotting analysis were used to evaluate the effect of some flavonoids present in a crude extract of polyphenols and the total extract of saponins on cell survival and apoptosis. Results Analysis of expression level of some gene (PIK3CA, PTEN, AKT1, mTOR, EIF4E, RPS6KB1, and TSC1) involved in the mTOR pathway and the phosphorylation of S6 and AKT proteins allowed to observe that a total Rhus tripartita extract and some of the compounds found in the extract controls THP-1 cell proliferation and apoptosis via regulation of the PI3K-Akt-mTOR signaling pathway. Conclusion Rhus tripartita-induced inhibition of cell cycle and induction of apoptosis may involve the mTOR pathway. Therefore, Rhus tripartita extract may be a useful candidate as a natural anti-cancer drug to support the treatment of AML.

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The polyphenol/saponin-rich Rhus tripartita extract has an apoptotic effect on THP-1 cells through the PI3K/AKT/mTOR signaling pathway

10.21203/rs.3.rs-138978/v1 ◽

2021 ◽

Author(s):

Hajer Tlili ◽

Anca Macovei ◽

Daniela Buonocore ◽

Manuela Lanzafame ◽

Hanen Najjaa ◽

...

Keyword(s):

Signaling Pathway ◽

Plant Extract ◽

Therapeutic Potential ◽

Mtor Pathway ◽

Mtor Signaling ◽

Cellular Growth ◽

Cancer Drug ◽

Mtor Signaling Pathway ◽

Epicatechin Gallate ◽

Saponin Content

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Total saponins of Bolbostemma paniculatum (maxim.) Franquet exert antitumor activity against MDA-MB-231 human breast cancer cells via inhibiting PI3K/Akt/mTOR pathway

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-019-2708-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Jian-Wei Dou ◽

Rong-Guo Shang ◽

Xiao-Qin Lei ◽

Kang-Le Li ◽

Zhan-Zi Guo ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Mtor Inhibitor ◽

Therapeutic Potential ◽

Underlying Mechanism ◽

Mtor Pathway ◽

Mtor Signaling ◽

Pi3k Inhibitor ◽

Mtor Signaling Pathway ◽

And Migration

Abstract Background The aim of the present study was to examine the effects of the Bolbostemma paniculatum (Maxim.) Franquet (BP) active compound, BP total saponins (BPTS), on MDA-MB-231 cells, and investigate the underlying mechanism regarding BPTS-mediated attenuation of the PI3K/Akt/mTOR pathway. Methods The effect of BPTS on cytotoxicity, induction of apoptosis and migration on MDA-MB-231 cells at three different concentrations was investigated. A CCK-8 assay, wound-healing assay and flow cytometry were used to demonstrate the effects of BPTS. Additionally, expression of the primary members of the PI3K/Akt/mTOR signaling pathway was assessed using western blotting. To verify the underlying mechanisms, a PI3K inhibitor and an mTOR inhibitor were used. Results BPTS inhibited proliferation of MDA-MB-231 cells with an IC50 value of 10 μg/mL at 48 h. BPTS inhibited migration of MDA-MB-231 cells, and the western blot results demonstrated that BPTS reduced p-PI3K, p-Akt and p-mTOR protein expression levels in MDA-MB-231 cells. Additionally, the results were confirmed using a PI3K inhibitor and an mTOR inhibitor. BPTS decreased proliferation and migration of MDA-MB-231 cells possibly through inhibiting the PI3K/Akt/mTOR signaling pathway. Conclusions The results highlight the therapeutic potential of BPTS for treating patients with triple-negative breast cancer.

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Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

Current Medicinal Chemistry ◽

10.2174/0929867327666200504081503 ◽

2020 ◽

Vol 27 ◽

Author(s):

Naser-Aldin Lashgari ◽

Nazanin Momeni Roudsari ◽

Saeideh Momtaz ◽

Negar Ghanaatian ◽

Parichehr Kohansal ◽

...

Keyword(s):

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

In Vivo Studies ◽

Cochrane Library ◽

Mtor Signaling Pathway ◽

Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

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Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway

Pharmacological Research ◽

10.1016/j.phrs.2019.104626 ◽

2020 ◽

Vol 152 ◽

pp. 104626 ◽

Cited By ~ 10

Author(s):

Ana Sanches-Silva ◽

Lara Testai ◽

Seyed Fazel Nabavi ◽

Maurizio Battino ◽

Kasi Pandima Devi ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Signaling Pathway ◽

Therapeutic Potential ◽

Mtor Signaling ◽

Mtor Signaling Pathway

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Emerging Role of mTOR Signaling-Related miRNAs in Cardiovascular Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/6141902 ◽

2018 ◽

Vol 2018 ◽

pp. 1-23 ◽

Cited By ~ 7

Author(s):

Arun Samidurai ◽

Rakesh C. Kukreja ◽

Anindita Das

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Signaling Pathway ◽

Noncoding Rna ◽

Current Knowledge ◽

Mammalian Target Of Rapamycin ◽

Vital Role ◽

Mtor Signaling ◽

Cellular Growth ◽

Mtor Signaling Pathway

Mechanistic/mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase of the phosphoinositide 3-kinase- (PI3K-) related kinase family, elicits a vital role in diverse cellular processes, including cellular growth, proliferation, survival, protein synthesis, autophagy, and metabolism. In the cardiovascular system, the mTOR signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of both physiological and pathological processes. MicroRNAs (miRs), a class of short noncoding RNA, are an emerging intricate posttranscriptional modulator of critical gene expression for the development and maintenance of homeostasis across a wide array of tissues, including the cardiovascular system. Over the last decade, numerous studies have revealed an interplay between miRNAs and the mTOR signaling circuit in the different cardiovascular pathophysiology, like myocardial infarction, hypertrophy, fibrosis, heart failure, arrhythmia, inflammation, and atherosclerosis. In this review, we provide a comprehensive state of the current knowledge regarding the mechanisms of interactions between the mTOR signaling pathway and miRs. We have also highlighted the latest advances on mTOR-targeted therapy in clinical trials and the new perspective therapeutic strategies with mTOR-targeting miRs in cardiovascular diseases.

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The Combination Treatment of Curcumin and Probucol Protects Chondrocytes from TNF-α Induced Inflammation by Enhancing Autophagy and Reducing Apoptosis via the PI3K-Akt-mTOR Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5558066 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Guangtao Han ◽

Yubiao Zhang ◽

Haohuan Li

Keyword(s):

Signaling Pathway ◽

Combination Treatment ◽

Inflammatory Cytokine ◽

Combined Treatment ◽

Mtor Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Tnf Α

Osteoarthritis (OA) is a chronic joint disease characterized by cholesterol accumulation in chondrocytes, cartilage degeneration, as well as extracellular matrix (ECM) destruction, and joint dysfunction. Curcumin, a chemical that can reduce cholesterol levels in OA patients, also can inhibit the progression of OA. However, a high concentration of curcumin may also trigger apoptosis in normal chondrocytes. Besides curcumin, probucol that is found can also effectively decrease the cholesterol level in OA patients. Considering that high cholesterol is a risk factor of OA, it is speculated that the combination treatment of curcumin and probucol may be effective in the prevention of OA. To investigate the possible effects of such two chemicals on OA pathophysiology, chondrocyte apoptosis and autophagy behavior under inflammatory cytokine stress were studied, and specifically, the PI3K-Akt-mTOR signaling pathway was studied. Methods. Cell proliferation, colony formation, and EdU assay were performed to identify the cytotoxicity of curcumin and probucol on chondrocytes. Transwell assay was conducted to evaluate chondrocyte migration under TNF-α inflammation stress. Immunofluorescence, JC-1, flow cytometry, RT-PCR, and western blot were used to investigate the signal variations related to autophagy and apoptosis in chondrocytes and cartilage. A histological study was carried out on OA cartilage. Glycosaminoglycan (GAG) release was determined to evaluate the ECM degradation under stress. Results. Compared with a single intervention with curcumin or probucol, a combined treatment of these two chemicals is more effective in terms of protecting chondrocytes from stress injury induced by inflammatory cytokines. The promoted protection may be attributed to the inhibition of apoptosis and the blockage of the autophagy-related PI3K/Akt/mTOR pathway. Such results were also verified in vitro by immunofluorescence staining of OA chondrocytes and in vivo by immunohistochemistry staining of cartilage. Besides, in vivo studies also showed that when applied in combination, curcumin and probucol could block the PI3K-AKT-mTOR signaling pathway; promote COL-II expression; suppress P62, MMP-3, and MMP-13 expression; and inhibit TNF-α-stimulated cartilage degradation. Moreover, the combined medication could help reduce the release of ECM GAGs in OA cartilage and alleviate the severity of OA. Conclusion. A combined treatment of curcumin and probucol could be used to protect chondrocytes from inflammatory cytokine stress via inhibition of the autophagy-related PI3K/Akt/mTOR pathway both in vitro and in vivo, which might be of potential pharmaceutical value for OA prevention and therapy.

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Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway

Cell Death and Disease ◽

10.1038/s41419-020-03357-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shaohong Fang ◽

Xin Wan ◽

Xiaoyi Zou ◽

Song Sun ◽

Xinran Hao ◽

...

Keyword(s):

Arsenic Trioxide ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Early Stage ◽

Mtor Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Pi3k Inhibitor Ly294002 ◽

Vascular Stents ◽

Atherosclerotic Lesions

AbstractInducing autophagy and inhibiting apoptosis may provide a therapeutic treatment for atherosclerosis (AS). For the treatment of progressive AS, arsenic trioxide (ATO) has been used to coat vascular stents. However, the effect of ATO on autophagy of macrophages is still unknown. Therefore, the aims of this study were to characterize the effects and the mechanism of actions of ATO on autophagy in macrophages. Our results showed that ATO-induced activation of autophagy was an earlier event than ATO-induced inhibition of the expression of apoptosis markers in macrophages and foam cells. Nuclear transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy and promoting lysosomal biogenesis. Here, we report that ATO triggered the nuclear translocation of TFEB, which in turn promoted autophagy and autophagosome-lysosome fusion. Both the latter events were prevented by TFEB knockdown. Moreover, ATO decreased the p-AKT and p-mTOR in the PI3K/AKT/mTOR signaling pathway, thus inducing autophagy. Correspondingly, treatment with the autophagy inhibitor 3-methyladenine (3-MA) abolished the autophagy-inducing effects of ATO. Meanwhile, PI3K inhibitor (LY294002) and mTOR inhibitor (rapamycin) cooperated with ATO to induce autophagy. Furthermore, reactive oxygen species (ROS) were generated in macrophages after treatment with ATO. The ROS scavenger N-acetyl-1-cysteine (NAC) abolished ATO-induced nuclear translocation of TFEB, as well as changes in key molecules of the AKT/mTOR signaling pathway and downstream autophagy. More importantly, ATO promoted autophagy in the aorta of ApoE−/− mice and reduced atherosclerotic lesions in early AS, which were reversed by 3-MA treatment. In summary, our data indicated that ATO promoted ROS induction, which resulted in nuclear translocation of TFEB and inhibition of the PI3K/AKT/mTOR pathway. These actions ultimately promoted macrophage autophagy and reduced atherosclerotic lesions at early stages. These findings may provide a new perspective for the clinical treatment of early-stage atherosclerosis and should be further studied.

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Beneficial Effects of Resveratrol-Mediated Inhibition of the mTOR Pathway in Spinal Cord Injury

Neural Plasticity ◽

10.1155/2018/7513748 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Jingying Zhou ◽

Xue Huo ◽

Benson O. A. Botchway ◽

Luyao Xu ◽

Xiaofang Meng ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

High Rate ◽

Mtor Signaling Pathway ◽

Beneficial Effects ◽

Cord Injury

Spinal cord injury (SCI) causes a high rate of morbidity and disability. The clinical features of SCI are divided into acute, subacute, and chronic phases according to its pathophysiological events. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cell death and inflammation in the acute phase and neuroregeneration in the subacute/chronic phases at different times. Resveratrol has the potential of regulating cell growth, proliferation, metabolism, and angiogenesis through the mTOR signaling pathway. Herein, we explicate the role of resveratrol in the repair of SCI through the inhibition of the mTOR signaling pathway. The inhibition of the mTOR pathway by resveratrol has the potential of serving as a neuronal restorative mechanism following SCI.

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Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Leukemia ◽

10.1038/leu.2013.226 ◽

2013 ◽

Vol 28 (4) ◽

pp. 739-748 ◽

Cited By ~ 62

Author(s):

L M Neri ◽

A Cani ◽

A M Martelli ◽

C Simioni ◽

C Junghanss ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Signaling Pathway ◽

Therapeutic Potential ◽

Lymphoblastic Leukemia ◽

Mtor Signaling ◽

Mtor Signaling Pathway

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Glucose-induced lipid deposition in goose primary hepatocytes is dependent on the PI3K-Akt-mTOR signaling pathway

Archives of Biological Sciences ◽

10.2298/abs151210075h ◽

2016 ◽

Vol 68 (4) ◽

pp. 853-861

Author(s):

Chunchun Han ◽

Shouhai We ◽

Fang He ◽

Song Qi ◽

Xiangping Xiong ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Signaling Pathway ◽

Fatty Acid Oxidation ◽

Mtor Pathway ◽

Mtor Signaling ◽

Acid Oxidation ◽

Lipid Deposition ◽

Mtor Signaling Pathway ◽

Primary Hepatocytes

Previously we showed that fatty liver formation in overfed geese was accompanied by PI3K-Akt-mTOR pathway activation and changes in plasma glucose concentrations. Here, we show that glucose acts in goose hepatocellular lipid metabolism through the PI3K-Akt-mTOR signaling pathway. We observed that glucose increased lipogenesis, decreased fatty acid oxidation and increased very low density lipoprotein triglyceride (VLDL-TG) assembly and secretion. Co-treatment with glucose and inhibitors of the PI3K-Akt-mTOR pathway (LY294002, rapamycin, NVP-BEZ235) decreased the levels of factors involved in lipogenesis and increased the levels of factors involved in fatty acid oxidation and VLDL-TG assembly and secretion. These findings show that inhibition of the PI3K-Akt-mTOR pathway decreased glucose-induced lipogenesis, inhibited the downregulation of fatty acid oxidation by glucose and increased the upregulation of VLDL-TG assembly and secretion by glucose. The results presented herein provide further support for the role of the PI3K-Akt-mTOR pathway in lipid metabolism as we showed that in goose primary hepatocytes, glucose acts through the PI3K-Akt-mTOR-dependent pathway to stimulate lipid deposition by increasing lipogenesis and decreasing fatty acid oxidation and VLDL-TG assembly and secretion.

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