Abstract:Whereas hypertension, diabetes, and dyslipidemia are age-related risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), aging alone is an independent risk factor. With advancing age, the heart and kidney gradually but significantly undergo inflammation and subsequent fibrosis, which eventually results in an irreversible decline in organ physiology. Through cardiorenal network interactions, cardiac dysfunction leads to and responds to renal injury, and both facilitate aging effects. Thu… Show more
“…As shown in Figure D, celastrol (0 or 4 µmol/L) changed TFK‐1 and HuCCT‐1 cells morphology to round, epithelioid phenotype from fibroblast‐like mesenchymal phenotype. We next assessed the EMT‐related proteins, including matrix metalloproteinases (MMPs), E‐cadherin, and vimentin, which promote tumor cell invasion . As expected, western blotting in Figure E suggested that MMP 2, 9, and vimentin proteins expression were obviously decreased, nevertheless the E‐cadherin was upregulated after celastrol incubation.…”
Aim: Cholangiocarcinoma is a malignant tumor originating from bile duct epithelium. Currently, the treatment strategy is very limited and the prognosis is poor.Recent studies reported celastrol exhibits antigrowth and antimetastasis properties in many tumors. Our study aimed to assess the anti-CCA effects of cholangiocarcinoma (CCA) and the mechanisms involved in it. Methods: In this study, the long-term and short-term antiproliferation effects was determined using colony formation and Cell Counting Kit-8 (CCK-8) assays, respectively. Flow cytometry was performed to quantify apoptosis. Furthermore, wound healing and transwell assays were performed to determine the cell migration and invasion capabilities, respectively. To further find the mechanism involved in the celastrol-induced biological functions, LY204002, a PI3K/Akt signaling inhibitor, and an Akt-1 overexpression plasmid were employed to find whether PI3K/Akt pathway was involved in the celastrol-induced CCA cell inhibition. Additionally, short interfering RNA (siRNA) was also used to investigate the mechanism involved in the celastrol-induced PI3K/Akt signaling inhibition. Western blotting and immunofluorescence assays were also performed to detect the degree of relative proteins.Moreover, we validated the antiproliferation and antimetastasis effects of celastrol in vivo by constructing subcutaneous and lung metastasis nude mice models. Results: We discovered that celastrol effectively induced apoptotic cell death and inhibited the capacity of migration and invasion in CCA cells. Further mechanistic study identified that celastrol regulated the PI3K/Akt signaling pathway, and the antitumor efficacy was likely due to the upregulation of PTEN, a negative regulator of PI3K/Akt. Blockage of PTEN abolished the celastrol-induced PI3K/Akt signaling inhibition. Additionally, in vivo experiments conformed celastrol inhibited the tumor growth and lung metastasis with no serious side effects. Conclusions: Overall, our study elucidated a mechanistic framework for the anti-CCA effects of celastrol via PTEN/PI3K/Akt pathway. 784 | ZHU and WEI K E Y W O R D S Akt, apoptosis, celastrol, epithelial-to-mesenchymal transition, phosphatase and tensin homolog
“…As shown in Figure D, celastrol (0 or 4 µmol/L) changed TFK‐1 and HuCCT‐1 cells morphology to round, epithelioid phenotype from fibroblast‐like mesenchymal phenotype. We next assessed the EMT‐related proteins, including matrix metalloproteinases (MMPs), E‐cadherin, and vimentin, which promote tumor cell invasion . As expected, western blotting in Figure E suggested that MMP 2, 9, and vimentin proteins expression were obviously decreased, nevertheless the E‐cadherin was upregulated after celastrol incubation.…”
Aim: Cholangiocarcinoma is a malignant tumor originating from bile duct epithelium. Currently, the treatment strategy is very limited and the prognosis is poor.Recent studies reported celastrol exhibits antigrowth and antimetastasis properties in many tumors. Our study aimed to assess the anti-CCA effects of cholangiocarcinoma (CCA) and the mechanisms involved in it. Methods: In this study, the long-term and short-term antiproliferation effects was determined using colony formation and Cell Counting Kit-8 (CCK-8) assays, respectively. Flow cytometry was performed to quantify apoptosis. Furthermore, wound healing and transwell assays were performed to determine the cell migration and invasion capabilities, respectively. To further find the mechanism involved in the celastrol-induced biological functions, LY204002, a PI3K/Akt signaling inhibitor, and an Akt-1 overexpression plasmid were employed to find whether PI3K/Akt pathway was involved in the celastrol-induced CCA cell inhibition. Additionally, short interfering RNA (siRNA) was also used to investigate the mechanism involved in the celastrol-induced PI3K/Akt signaling inhibition. Western blotting and immunofluorescence assays were also performed to detect the degree of relative proteins.Moreover, we validated the antiproliferation and antimetastasis effects of celastrol in vivo by constructing subcutaneous and lung metastasis nude mice models. Results: We discovered that celastrol effectively induced apoptotic cell death and inhibited the capacity of migration and invasion in CCA cells. Further mechanistic study identified that celastrol regulated the PI3K/Akt signaling pathway, and the antitumor efficacy was likely due to the upregulation of PTEN, a negative regulator of PI3K/Akt. Blockage of PTEN abolished the celastrol-induced PI3K/Akt signaling inhibition. Additionally, in vivo experiments conformed celastrol inhibited the tumor growth and lung metastasis with no serious side effects. Conclusions: Overall, our study elucidated a mechanistic framework for the anti-CCA effects of celastrol via PTEN/PI3K/Akt pathway. 784 | ZHU and WEI K E Y W O R D S Akt, apoptosis, celastrol, epithelial-to-mesenchymal transition, phosphatase and tensin homolog
“…It has been reported that the myofibroblasts are contractile and augment the deposition of the extracellular matrix, which leads to progressive interstitial fibrosis. This process is enhanced by the decrease of ECM degradation[14]. MMP9 is of one the important enzyme which could degrade extracellular matrix, which is regulated by TIMP1[15–17], so we detected the expression of MMP9 and TIPM1 in UUO model.…”
35Emodin has a variety of pharmacological functions including anti-bacterial infection, 36 anti-inflammatory, anti-oxidation, anti-tumor, regulation of gastrointestinal activities 37 and anti-hepatic and lung fibrosis. However, the role of emodin in the regulation of 38 renal interstitial fibrosis(RIF) remains poorly understood. In this study, we 39 investigated the regulation of emodin in RIF and revealed the underlying molecular 40 mechanisms. We established a unilateral ureter obstruction(UUO) model to simulate 41 renal interstitial fibrosis in rats. We found that UUO rats were observed a large 42 amount of inflammatory cell infiltration, more fibroblast proliferation, collagen fiber 43 proliferation. Furthermore, we demonstrated that the up-regulation of TIMP1 and 44 down-regulation of MMP9 were related to renal fibrosis. However, those phenomena 45 in emodin-treated UUO rats were ameliorated. Collectively, our results provide new 46 insights into the treatment of RIF and suggest that the TIMP1/MM9 signaling axis 47 may be a potential therapeutic target for RIF. 48 49 Introduction 53 Renal Interstitial Fibrosis(RIF) is a hallmark of pathological progression from to renal 54 injuries to a variety of Chronic Kidney Disease(CDK)[1, 2]. CKD affects over 10% of 55 the worldwide population with high mortality, due to limited available or affordable 56 treatment partly. What's more, the number will further increase according to the 57 increased number of elderly people and increased prevalence of major disease which 58 leads to CKD like obesity, diabetes, atherosclerosis and hypertension[3-5]. Because 59 RIF is considered as the underlying pathological process of chronic CKD, therefore, it 60 is necessary to discover and identify the novel and specific treatment to inhibit 61 3 fibrosis and ameliorates CDK. 62 63 Fibrosis is defined by excessive accumulation of extracellular matrix(ECM) mainly 64 produced by tissue resident mesenchymal cells, accompany with tissue regeneration 65 and inflammation. In normal kidney, the production and degradation of ECM are 66 dynamic and in balance, but the balance is broken in fibrotic ECM[2]. The ECM is 67 controlled by matrix metalloproteinases (MMPs) and tissue inhibitors of 68 metalloproteinases (TIMPs). MMPs are the major enzymes implicated in ECM 69 degradation. It is reported that four forms of TIMPs all are expressed in kidney, but 70 only TIMP1/2 inhibits MMPs expression. MMP9 is an important member of the 71 MMPs family. It participates in the degradation of ECM, regulation the synthesis and 72 metabolic balance of ECM under physiological and pathological conditions. TIMP1 73 specifically blocks MMP-9 activity, which plays a key role in ECM accumulation and 74 degradation while TIMP-2 involves in regulation of MMP-2 activity[6-8]. 75 76 Emodin is an anthraquinone compound extracted from rhubarb and has a wide range 77 of pharmacological effects. In liver fibrosis, recent studies showed that Emodin 78 alleviates CCl4-induced by suppressing EMT and transforming growth fa...
“…Among MMPs expressed in adult kidneys, MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-14 have been extensively studied. 62 The pathological mechanism by which high free activated MMPs levels alter the renal tissue is complex; briefly, it could be held related to an increase of local markers of inflammation that leads to upregulation of kidney fibrosis by promoting ECM production ( Figure 2 ). Figure 2 Schematic representation of pathogenic mechanisms by which matrix metalloproteinases (MMPs) might lead to renal damage.…”
Section: Mmps In Hypertension-mediated Renal Impairmentmentioning
Matrix metalloproteinases (MMPs) are important extracellular enzymes involved in many physiological and pathological processes. Changes in the activity and concentration of specific MMPs, as well as the unbalance with their inhibitors (tissue inhibitors of metalloproteinases – TIMPs), have been described as a part of the pathogenic cascade promoted by arterial hypertension. MMPs are able to degrade various protein substrates in the extracellular matrix, to influence endothelial cells function, vascular smooth muscle cells migration, proliferation and contraction, and to stimulate cardiomyocytes changes. All these processes can be activated by chronically elevated blood pressure values. Animal and human studies demonstrated the key function of MMPs in the pathogenesis of hypertension-mediated vascular, cardiac, and renal damage, besides age and blood pressure values. Thus, the role of MMPs as biomarkers of hypertension-mediated organ damage and potential pharmacological treatment targets to prevent further cardiovascular and renal complications in hypertensive population is increasingly supported. In this review, we aimed to describe the main scientific evidence about the behavior of MMPs in the development of vascular, cardiac, and renal damage in hypertensive patients.
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