Higenamine Improves Cardiac and Renal Fibrosis in Rats With Cardiorenal Syndrome via ASK1 Signaling Pathway

Deng, Ting; Wei, Zhenming; Gael, Akindavyi; Deng, Xiaofang; Liu, Yunfeng; Lai, Jun; Hang, Lifeng; Yan, Quan-neng; Fu, Qiang; Li, Zhiliang

doi:10.1097/fjc.0000000000000822

Cited by 12 publications

(8 citation statements)

References 33 publications

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“…For example, Deng et al presented that higenamine may target the ASK1/MAPK (ERK and P38)/NF- κ B signaling pathway to improve cardiorenal function and alleviate cardiac and renal fibrosis in CRS rats. In addition, higenamine was also found to significantly inhibit the protein expression of mitogen-activated protein kinase (MAPK) (ERK and P38)/NF- κ B pathway in CRS rats and then to protect rat cardiomyocytes [ 30 ]. Cai et al discovered that melatonin and exendin-4 treatment exerted protective effects on the heart of CRS rats through the TNF- α /NF- κ B/MMP-2/MMP-9/IL-1 β pathway [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Poricoic Acid A Inhibits the NF-κB/MAPK Pathway to Alleviate Renal Fibrosis in Rats with Cardiorenal Syndrome

Chen

Zhang²,

Huang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. To explore the potential and mechanism of action of poricoic acid A (PAA) in treatment of cardiorenal injury and fibrosis due to cardiorenal syndrome (CRS). Materials and Methods. A CRS rat model was established by transabdominal subtotal nephrectomy (STNx). The experimental group was treated by gavage of PAA (10 mg/kg/day). After 8 weeks of treatment, echocardiography was utilized for detecting heart-related indexes in rats. HE and Masson staining were conducted to detect the degree of pathological damage and fibrosis in rat kidney tissue, respectively. In addition, serum blood urea nitrogen (BUN), serum creatinine (SCr), and 24-hour urine protein were measured biochemically. Also, the levels of inflammatory factors (IL-1β, IL-6, and IL-10) in rat kidneys were measured using ELISA. Western blot was used to examine the expression of NF-κB/MAPK pathway-related proteins. Results. In this study, a CRS rat model was successfully established by STNx surgery. PAA treatment could significantly alleviate the damage of heart and kidney function in CRS rats and reduce the pathological damage of kidney tissue and renal fibrosis. Meanwhile, PAA could also inhibit the renal inflammatory response through downregulating IL-1β and IL-6 levels in the kidney tissue and upregulating IL-10 level. Further mechanism exploration showed that the NF-κB/MAPK signaling pathway was significantly activated in CRS rats, while PAA treatment could markedly inhibit the NF-κB/MAPK signaling pathway activity in CRS rats. Conclusion. PAA can obviously improve the pathological damage and fibrosis of renal tissue in CRS rats and maintain the function of the heart and kidney. The above functions of PAA may be achieved by inhibiting the NF-κB/MAPK signaling pathway activity. Briefly speaking, PAA can serve as a potential drug for CRS treatment.

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Section: Discussionmentioning

confidence: 99%

Poricoic Acid A Inhibits the NF-κB/MAPK Pathway to Alleviate Renal Fibrosis in Rats with Cardiorenal Syndrome

Chen

Zhang²,

Huang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…These results indicated that higenamine improves cardiomyocyte fibrosis and dysfunction by inhibiting TGF-β1/Smad signaling and cardiac fibroblasts activation. Deng et al (2020) , also found that higenamine dramatically inhibits the collagen synthesis of NRCF and inhibits the hypertrophy of neonatal rat cardiomyocytes. It mainly mediates ASK1 pathways to relieve cell fibrosis ( Table 3 ).…”

Section: Effects Of Higenamine On Heart Disease In Vitromentioning

confidence: 89%

“…Currently, higenamine is considered to be effective in the treatment of CRS. A study from Deng ( Deng et al, 2020 ) revealed that compared with type 2 CRS rats, rats treated with higenamine (0.5–4.5 mg kg −1 ) showed significantly increased LV ejection fraction (LVEF%) and left ventricular fraction shortening (LVFS%), decreased LV end systolic volume (LVESV), LV posterior wall thickness LVPW, Cardiac weight index (CWI) and kidney weight index (KWI). In addition, higenamine markedly decreased serum creatinine (Scr), blood urea nitrogen (BUN), indole sulfate (IS), and 24-h urine protein level as well as memorably diminished cardiac and renal fibrosis in CRS rats, accompanied with the reduced protein level of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and collagen I.…”

Section: Effects Of Higenamine On Heart Disease In Vivomentioning

confidence: 99%

“…In addition, higenamine significantly inhibits the relative protein expression of p-ASK1, MAPK, ERK, p38, and NF-kB in the heart tissues of CRS rats and cardiomyocytes. Thus, higenamine improves the heart and kidney function of CRS rats by targeting the ASK1/MAPK (ERK, P38)/NF-kB signaling pathway ( Deng et al, 2020 ). Higenamine inhibits the apoptosis biochemical markers caspase 3 and 9 in primary neonatal rats and adult mouse ventricular myocytes.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

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Role of Higenamine in Heart Diseases: A Mini-Review

Wen

Zhang

et al. 2022

Front. Pharmacol.

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Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

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“…The p38 MAPK is stimulated and activated by cytokines and environmental stress and belongs to stress-activated protein kinases, which are involved in regulating cell proliferation, differentiation, and apoptosis [ 26 ]. ASK1, a member of the MAP3K family, is ROS-sensitive and is a key gene in oxidative stress-mediated apoptosis [ 27 ]. After oxidative stress, the Thr 845 site of ASK1 is phosphorylated and then activated, and activated ASK1 can phosphorylate downstream MKK4 and MKK7, which can phosphorylate downstream MKK3 and MKK6, which activate p38 by phosphorylating Thr180 and Tyr182 [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Mechanism of Realgar against Esophageal Cancer Based on Ferroptosis Induced by ROS-ASK1-p38 MAPK Signaling Pathway

Yang

Chen

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Realgar (REA), a Chinese herbal decoction, has been used to treat various tumors and has produced positive outcomes; however, there is a lack of convincing evidence for the treatment of esophageal cancer. The present study aimed to investigate the effects of REA on esophageal cancer (EC) and explore its mechanism. Methods. EC cells Eca109 and KYSE150 were selected for this study, and different groups of treated cells were set up. We studied the inhibition rate and half inhibition concentration (IC50) by CCK-8 method, the clone formation assay was used to detect the clone formation ability, the scratch assay is used to determine the cell migration ability, the Transwell assay was used to detect the cell invasion ability, the protein expressions of E-cadherin, Slug, N-cadherin, ASK1, p38 MAPK, p-p38 MAPK, and GPX4 were determined using Western blot, the mRNA expressions of ASK1 and p38 MAPK were assessed using qRT-PCR, transmission electron microscopy was used to observe the cellular ultrastructure, Prussian blue staining was used to observe the intracellular iron particle distribution, and biochemical analysis of cellular MDA, SOD, GSH, and GPXS activities, flow cytometric analysis of cellular ROS levels, immunofluorescence staining to detect cellular GPX4 expression, and JC-1 method to detect mitochondrial membrane potential were used. Results. REA inhibited the proliferation of Eca109 and KYSE150 cells in a time- and concentration-dependent manner, and REA significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and activated the cellular ferroptosis and ROS-ASK1-p38 MAPK signaling pathways ( P < 0.05 ). Inhibition of activation of the ROS-ASK1-p38 MAPK signaling pathway promoted the inhibition of proliferation, migration, and invasion of Eca109 and KYSE150 cells and the induction of ferroptosis by REA. Conclusion. REA induced ferroptosis and inhibited the migration of EC cells by activating the ROS-ASK1-p38 MAPK signaling pathway.

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Higenamine Improves Cardiac and Renal Fibrosis in Rats With Cardiorenal Syndrome via ASK1 Signaling Pathway

Cited by 12 publications

References 33 publications

Poricoic Acid A Inhibits the NF-κB/MAPK Pathway to Alleviate Renal Fibrosis in Rats with Cardiorenal Syndrome

Poricoic Acid A Inhibits the NF-κB/MAPK Pathway to Alleviate Renal Fibrosis in Rats with Cardiorenal Syndrome

Role of Higenamine in Heart Diseases: A Mini-Review

Exploring the Mechanism of Realgar against Esophageal Cancer Based on Ferroptosis Induced by ROS-ASK1-p38 MAPK Signaling Pathway

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