scholarly journals Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Tao Wang ◽  
Yanbin Gao ◽  
Rongchuan Yue ◽  
Xiaolei Wang ◽  
Yimin Shi ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Diabetic Rats ◽  
Therapeutic Effects ◽  
Ginsenoside Rg1 ◽  
Podocyte Injury ◽  
Therapeutic Function ◽  
Polymerase Chain ◽  
Underlying Mechanisms

Background. Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. Methods. In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. Results. Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. Conclusion. Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN.

scholarly journals Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Guo Zu ◽  
Jing Guo ◽  
Ningwei Che ◽  
Tingting Zhou ◽  
Xiangwen Zhang
Keyword(s):  
Signaling Pathway ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Ginsenoside Rg1 ◽  
Intestinal Ischemia Reperfusion

Abstract Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury.

scholarly journals Photodynamic Therapy Enhanced the Antitumor Effects of Berberine on HeLa Cells

2019 ◽  
Vol 17 (1) ◽  
pp. 413-421 ◽  
Author(s):  
Han-Qing Liu ◽  
Ya-Wen An ◽  
A-Zhen Hu ◽  
Ming-Hua Li ◽  
Guang-Hui Cui
Keyword(s):  
Photodynamic Therapy ◽  
Western Blot ◽  
Hela Cells ◽  
Mammalian Target Of Rapamycin ◽  
Control Group ◽  
Antitumor Effects ◽  
Underlying Mechanisms ◽  
And Control

AbstractIn this study we investigated the antineoplastic effects of Berberine (BBR)-mediated photodynamic therapy (PDT) on HeLa cells and its related mechanisms. The CCK-8 assay and flow cytometry were used to evaluate the proliferation and apoptosis of cells respectively. In addition, changes in protein expression levels were assessed using western blot. BBR at dose of 10 mg/kg was injected intraperitoneally to mice with tumors and PDT treatments were performed 24 hours later. In vivo imaging systems were used to evaluate the fluorescence of BBR. In vitro, PDT significantly enhanced the effects of BBR on inducing cell apoptosis and inhibiting proliferation. The in vivo results showed that the fluorescence intensity in the PDT group was decreased compared with that in the BBR group. Tumor weights and tumor size in the PDT group were less than those in the control group; however, when BBR was applied without PDT, no significant differences were observed between the BBR and control group. The results of western blot showed that PDT enhanced the inhibitory effects of BBR on the mammalian target of rapamycin (mTOR) signaling pathway, that may partly explain the potential underlying mechanisms.

In Vitro and In Vivo Profiles and Characterization of Insulin Nanocarriers Based in Flexible Liposomes Designed for Oral Administration

2019 ◽  
Vol 16 (8) ◽  
pp. 948-960
Author(s):  
Sara Melisa Arciniegas Ruiz ◽  
María Josefa Bernad Bernad ◽  
Raquel Lopez Arellano ◽  
Roberto Diaz Torres ◽  
Sara Del Carmen Caballero Chacón ◽  
...  
Keyword(s):  
Polyacrylamide Gel Electrophoresis ◽  
Oral Route ◽  
Diabetic Rats ◽  
Release Profile ◽  
Therapeutic Effects ◽  
Subcutaneous Route ◽  
In Vivo Test ◽  
Glucose Levels

Background: Alternatives routes of delivery for Insulin have been evaluated to improve treatment for Diabetes Mellitus. The oral route is the most convenient physiologically; it releases in a similar way to endogenous secretion. Flexible liposomes have deformable abilities to pass through membranes with adequate therapeutic effects, but they have been tested only dermally. Objective: Our aim was to develop an oral nanocarrier based on flexible liposomes for insulin with polymer addition to reduce gastrointestinal degradation. Methods: Different percentages of polyethylene glycol were added to a conventional formulation of flexible liposomes. The manufacturing procedure was the heating method. Z potential, size particle, polydispersity index and encapsulation percentage were evaluated. A release profile was performed in the stomach and intestinal pH mediums by two-stage reverse dialysis method. The in-vivo test was performed in experimental diabetic rats by oral, transdermal and subcutaneous routes. Results: All the formulations showed polydispersity but adequate Z potential. The 10% PEG formulation obtained the best insulin enclosure with 81.9%. The insulin integrity after preparation was confirmed by polyacrylamide gel electrophoresis. PEG and non-PEG formulations showed similar behavior in acid release profile but the release and stability of lipid structures were better and longer in intestinal pH conditions. In vivo tests showed a reduction to normal glucose levels only in subcutaneous route. Conclusion: The polymer inclusion in flexible liposomes generates an adequate nanocarrier for proteins in terms of stability and composition; although its in-vivo use reduces glucose levels in subcutaneous route, the effect was not adequate in oral route.

scholarly journals AZD2014, A Dual mTOR Inhibitor, Attenuates Cardiac Hypertrophy in Vitro and in Vivo

2021 ◽  
Author(s):  
Byung-Hyun Cha ◽  
Minjin Jung ◽  
Angela S. Kim ◽  
Victoria C. Lepak ◽  
Brett A. Colson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Hypertrophy ◽  
Mammalian Target Of Rapamycin ◽  
Underlying Mechanism ◽  
Regulatory Function ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Cardiac Morbidity

Abstract Cardiac hypertrophy is one of the most common genetic heart disorders and considered a risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) pathway plays a key regulatory function in cardiovascular physiology and pathology in hypertrophy. AZD2014 is a small-molecule ATP competitive mTOR inhibitor working on both mTORC1 and mTORC2 complexes. Little is known about the therapeutic effects of AZD2014 in cardiac hypertrophy and its underlying mechanism. Here, AZD2014 is examined in in vitro model of phenylephrine (PE)-induced human cardiomyocyte hypertrophy and a myosin-binding protein-C (Mybpc3)-targeted knockout (KO) mouse model of cardiac hypertrophy. Our results demonstrate that cardiomyocytes treated with AZD2014 retain the normal phenotype and AZD2014 attenuates cardiac hypertrophy in the Mybpc3-KO mouse model through inhibition of dual mTORC1 and mTORC2, which in turn results in the down-regulation of the Akt/mTOR signaling pathway.

scholarly journals Mir-138 plays an important role in diabetic nephropathy through SIRT1-p38-TTP regulatory axis

2020 ◽  
Author(s):  
Fengxun Liu ◽  
Jia Guo ◽  
Yingjin Qiao ◽  
Shaokang Pan ◽  
Jiayu Duan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Experimental Methods ◽  
Therapeutic Effects ◽  
Key Factors ◽  
Regulatory Relationship ◽  
Podocyte Injury ◽  
P38 Pathway

Abstract Background : Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and is one of the most common and serious complications of diabetes mellitus (DM). SIRT1 and TTP are two important protective factors in DN, however, the regulatory relationship between SIRT1 and TTP and the underneath mechanism are interesting but still unclear. Identifying the key factors that regulate SIRT1 or TTP may be of great value to the understanding and treatment of the DN. Methods : in this study, through systematic experimental methods, we found that the expression of miR-138 was significantly up-regulated in DN clinical patients samples, and our experimental results suggested that miR-138 could bind the 3’UTR of SIRT1 and inhibit its expression in both cultured podocytes and db/db mice kidney tissues. Results : furthermore, our in vitro and in vivo date also indicated miR-138 could target SIRT1 and affect TTP through p38 pathway. And down-regulation of miR-138 attenuated podocyte injury and showed some extend of therapeutic effects in DN mice models. Conclusion : our findings reveal that the regulatory axis of miR-138-SIRT1-p38-TTP might play a key role in DN. We believe these findings may be of some value for deepening the understanding of DN and may serve as a reference for future treatment of this disease.

scholarly journals α-Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Mengqing Tao ◽  
Jia Jiang ◽  
Lin Wang ◽  
Yan Li ◽  
Qingcheng Mao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Raw 264.7 Cells ◽  
Therapeutic Effects ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Inflammatory Reactions ◽  
Hematological Analysis ◽  
Underlying Mechanisms

α-Mangostin (MAN) is a bioactive xanthone isolated from mangosteen. This study was designed to investigate its therapeutic effects on acute lung injury (ALI) and explore the underlying mechanisms of action. Rats from treatment groups were subject to oral administration of MAN for 3 consecutive days beforehand, and then ALI was induced in all the rats except for normal controls via an intraperitoneal injection with lipopolysaccharide. The severity of disease was evaluated by histological examination and hematological analysis. Protein expressions in tissues and cells were examined with immunohistochemical and immunoblotting methods, respectively. The levels of cytokines and nicotinamide adenine dinucleotide (NAD) were determined using ELISA and colorimetric kits, respectively. It was found that MAN treatment significantly improved histological conditions, reduced leucocytes counts, relieved oxidative stress, and declined TNF-α levels in ALI rats. Meanwhile, MAN treatment decreased expressions of nicotinamide phosphoribosyltransferase (NAMPT) and Sirt1 both in vivo and in vitro, which was accompanied with a synchronized decline of NAD and TNF-α. Immunoblotting assay further showed that MAN downregulated HMGB1, TLR4, and p-p65 in RAW 264.7 cells. MAN induced declines of both HMGB1/TLR4/p-p65 and TNF-α were substantially reversed by cotreatment with nicotinamide mononucleotide or NAD. These results suggest that downregulation of NAMPT/NAD by MAN treatments contributes to the alleviation of TLR4/NF-κB-mediated inflammations in macrophage, which is essential for amelioration of ALI in rats.

Everolimus shows synergistic antimyeloma effects with bortezomib via the AKT/mTOR pathway

2018 ◽  
Vol 67 (1) ◽  
pp. 39-47
Author(s):  
Jing Li ◽  
Zhaoyun Liu ◽  
Yanqi Li ◽  
Qian Jing ◽  
Honglei Wang ◽  
...  
Keyword(s):  
Mtor Inhibitor ◽  
Plasma Cells ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Mtor Pathway ◽  
Therapeutic Effects ◽  
Mice Model ◽  
Antitumor Effects

Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraproteins (M proteins). Everolimus works similarly to sirolimus as a mammalian target of rapamycin (mTOR) inhibitor. Bortezomib was the first therapeutic proteasome inhibitor to be tested in humans with MM. However, the combination of these two drugs for the treatment of MM has been rarely reported. In this study, we compared the therapeutic effects of everolimus and bortezomib, as well as those of a combination of everolimus and bortezomib, using an in vitro MM cell line model and in vivo xenograft mouse model. Our results showed that the synergistic antitumor effects of everolimus and bortezomib have significant inhibitory effect through inhibition of the AKT/mTOR pathway in both the MM cell lines and MM-bearing mice model. Our results provided evidence that the mTOR inhibitor, everolimus, will be a potential drug in MM therapy.

scholarly journals Effect of Tongxinluo on Nephrin Expression via Inhibition of Notch1/Snail Pathway in Diabetic Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Fangqiang Cui ◽  
Dawei Zou ◽  
Yanbin Gao ◽  
Na Zhang ◽  
Jinyang Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanism ◽  
High Glucose ◽  
Diabetic Rats ◽  
In Vitro Studies ◽  
Podocyte Injury ◽  
Snail Expression ◽  
Renal Structure

Podocyte injury is an important mechanism of diabetic nephropathy (DN). Accumulating evidence suggests that nephrin expression is decreased in podocyte in DN. Moreover, it has been demonstrated that tongxinluo (TXL) can ameliorate renal structure disruption and dysfunction in DN. However, the effect of TXL on podocyte injury in DN and its molecular mechanism is unclear. In order to explore the effect of TXL on podocyte injury and its molecular mechanism in DN, our in vivo and in vitro studies were performed. Our results showed that TXL increased nephrin expression in diabetic rats and in high glucose cultured podocyte. Meanwhile, TXL decreased ICN1 (the intracellular domain of notch), HES1, and snail expression in podocyte in vivo and in vitro. More importantly, we found that TXL protected podocyte from injury in DN. The results demonstrated that TXL inhibited the activation of notch1/snail pathway and increased nephrin expression, which may be a mechanism of protecting effect on podocyte injury in DN.

Anti-Angiongenic Effects of mTOR-Inhibitors Is Regulated by AKT Activity in Multiple Myeloma Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3406-3406
Author(s):  
Patrick Frost ◽  
Bao Hoang ◽  
Yijiang Shi ◽  
Huajun Yan ◽  
Alan Lichtenstein
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Mtor Inhibitors ◽  
Underlying Mechanisms ◽  
Salvage Pathways

Abstract Inhibitors of the mammalian target of rapamycin (mTOR), such as rapamycin (RAPA) and CCI-779 (CCI), have potential as anti-tumor agents against multiple myeloma (MM). Since other tumor models have demonstrated that heightened AKT activity induces hypersensitivity to mTOR inhibitors, we stably transfected U266 human MM cells with a constitutively activated AKT allele (U266-AKT) or empty vector control (U266-EV) in order to further explore the underlying mechanisms of this phenomena. Analysis of cell death demonstrated that U266-AKT were significantly more sensitive to RAPA in vitro, with an ED50 of 0.01 nM versus an ED50 of >100 nM for U266-EV control cells. A similar alteration of sensitivity to CCI was demonstrated in U266 isogenic tumors grown in NOD/SCID mice and treated with CCI in vivo. Analysis of the excised tumor nodules demonstrated a >5 fold inclease in apoptotic nuclei in U266-AKT tumors treated with CCI compared to isogenic control tumors, despite previous reports that mTOR inhibitors do not induce apoptosis in MM cells in vitro. One potential explanation for this is that AKT regulates the ability of CCI to inhibit angiogenesis, which is only relevent in vivo, and thereby indirectly induces apoptotic cell death. In support of this hypothesis, we demonstrated that CCI significantly decreased angiogenesis (measued by in situ staining of excised tumor nodules with CD34, a marker for endothelial cells) by 80% in U266-AKT, and only by 67% in isogenic controls. Since previous studies demonstrated that AKT/mTOR regulates the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1a (HIF1a), we hypothesized that MM cells with heightened AKT activity may be more sensitive to the CCI-mediated inhibition of these critical angiogenic factors. In vitro, RAPA was markedly more effective at inhibiting HIF-1a and VEGF expression from U266-AKT compared to U266-EV control cells. One possible explanation for the regulatory role of AKT in the RAPA/CCI response is that MM cells with hyperactive AKT function depend upon mTOR-mediated (i.e. cap-dependent) translational pathway to express critical proteins like VEGF and HIF-1a, while “low-AKT” MM cells may be able to utilize non-mTOR dependent (i.e. cap-independent) salvage pathways to express these critical proteins and are thereby resistant to mTOR inhibitors.

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