scholarly journals Selenium deficiency induces spleen pathological changes in pigs by decreasing selenoprotein expression, evoking oxidative stress, and activating inflammation and apoptosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shuang Li ◽  
Wenjuan Sun ◽  
Kai Zhang ◽  
Jiawei Zhu ◽  
Xueting Jia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Cytokines ◽  
The Body ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Antioxidant Systems ◽  
Tunel Staining ◽  
White Pulp ◽  
Sibling Pairs ◽  
Se Deficiency ◽  
Spleen Index

Abstract Background The immune system is one aspect of health that is affected by dietary selenium (Se) levels and selenoprotein expression. Spleen is an important immune organ of the body, which is directly involved in cellular immunity. However, there are limited reports on Se levels and spleen health. Therefore, this study established a Se-deficient pig model to investigate the mechanism of Se deficiency-induced splenic pathogenesis. Methods Twenty-four pure line castrated male Yorkshire pigs (45 days old, 12.50 ± 1.32 kg, 12 full-sibling pairs) were divided into two equal groups and fed Se-deficient diet (0.007 mg Se/kg) or Se-adequate diet (0.3 mg Se/kg) for 16 weeks. At the end of the trial, blood and spleen were collected to assay for erythroid parameters, the osmotic fragility of erythrocytes, the spleen index, histology, terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining, Se concentrations, the selenogenome, redox status, and signaling related inflammation and apoptosis. Results Dietary Se deficiency decreased the erythroid parameters and increased the number of osmotically fragile erythrocytes (P < 0.05). The spleen index did not change, but hematoxylin and eosin and TUNEL staining indicated that the white pulp decreased, the red pulp increased, and splenocyte apoptosis occurred in the Se deficient group. Se deficiency decreased the Se concentration and selenoprotein expression in the spleen (P < 0.05), blocked the glutathione and thioredoxin antioxidant systems, and led to redox imbalance. Se deficiency activated the NF-κB and HIF-1α transcription factors, thus increasing pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17, and TNF-α), decreasing anti-inflammatory cytokines (IL-10, IL-13, and TGF-β) and increasing expression of the downstream genes COX-2 and iNOS (P < 0.05), which in turn induced inflammation. In addition, Se-deficiency induced apoptosis through the mitochondrial pathway, upregulated apoptotic genes (Caspase3, Caspase8, and Bak), and downregulated antiapoptotic genes (Bcl-2) (P < 0.05) at the mRNA level, thus verifying the results of TUNEL staining. Conclusions These results indicated that Se deficiency induces spleen injury through the regulation of selenoproteins, oxidative stress, inflammation and apoptosis.

scholarly journals Oxidative stress in ageing

2017 ◽  
Vol 5 (11) ◽  
pp. 4826 ◽  
Author(s):  
Fasna K. A. ◽  
Geetha N. ◽  
Jean Maliekkal
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Free Radicals ◽  
Free Radical ◽  
Age Groups ◽  
The Body ◽  
Antioxidant Systems ◽  
Lipid Peroxidation Product ◽  
Free Radical Theory ◽  
Radical Theory

Background: Ageing is characterized by a gradual decline in body functions and decreased ability to maintain homeostasis. The free radical theory of ageing proposed by Harman D states that ageing is a result of cumulative damage incurred by free radical reactions. Free radicals are highly reactive molecular species with unpaired electrons; generated in the body by several physiological processes. Prime target to free radical attack are the polyunsaturated fatty acids of cell membranes causing lipid peroxidation. The free radicals are neutralized by the exogenous and endogenous antioxidant systems. Oxidative stress occurs when large number of free radicals are produced or the antioxidant activity is impaired. The present study is focused to find out the role of oxidative stress in ageing.Methods: A cross sectional observational study was undertaken to assess the oxidative stress in ageing; by determining the levels of lipid peroxidation product- malondialdehyde (MDA), the antioxidants- superoxide dismutase (SOD) and ceruloplasmin in various age groups. 150 healthy subjects were selected randomly and categorised into three different age groups of 20-30 years, 40-59 years and 60-90 years; with 50 subjects in each group. Results were expressed as mean ± standard deviation.Results: a significant elevation in serum MDA level and a decline in SOD were observed in 40-59 years and 60-90 years age groups. However, an elevated ceruloplasmin level was found in the above age groups.Conclusions: Aforementioned observations are suggestive of an association between oxidative stress and the progression of ageing process.

Oxidative Stress Is Associated With Cell Death, Wall Degradation, and Increased Risk of Rupture of the Intracranial Aneurysm Wall

Neurosurgery ◽  
2012 ◽  
Vol 72 (1) ◽  
pp. 109-117 ◽  
Author(s):  
Elisa Laaksamo ◽  
Riikka Tulamo ◽  
Arto Liiman ◽  
Marc Baumann ◽  
Robert M. Friedlander ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Caspase 9 ◽  
Tissue Samples ◽  
Aneurysm Wall ◽  
Increased Risk ◽  
Risk Of Rupture ◽  
High Oxidative Stress

Abstract BACKGROUND: The cause of rupture of intracranial aneurysms (IA) is not well understood. We previously demonstrated that loss of cells from the IA wall is associated with wall degeneration and rupture. OBJECTIVE: To investigate the mechanisms mediating cell death in the IA wall. METHODS: Snap-frozen tissue samples from aneurysm fundi were studied with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunostaining (14 unruptured and 20 ruptured), as well as with Western blot (12 unruptured and 12 ruptured). RESULTS: Ruptured IA walls had more TUNEL-positive cells than unruptured walls (P &lt; .001). Few cells positive for cleaved caspase-3 were detected. Cleaved caspase-9 (intrinsic activation of apoptosis) was significantly increased in ruptured IA walls, whereas cleaved caspase-8 (extrinsic activation of apoptosis) was not detected. Increased expression of hemeoxygenase-1, a marker for oxidative stress, was associated with IA wall degeneration and rupture. CONCLUSION: Our results show that programmed cell death is activated in the IA wall via the intrinsic pathway. High oxidative stress in the IA wall is probably a significant cause of the intrinsic activation of cell death.

scholarly journals Oxidative Stress, Antioxidant Defenses, COVID-19 and Pollution

2020 ◽  
Vol 8 (10) ◽  
Author(s):  
Selva Rivas-Arancibia ◽  
Jennifer Balderas-Miranda ◽  
Lizbeth Belmont-Zúñiga ◽  
Martín Martínez-Jáquez ◽  
Eduardo Hernández-Orozco ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Trace Elements ◽  
Immune System ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
The Body ◽  
Antioxidant Defenses ◽  
Cochrane Library ◽  
Antioxidant Systems ◽  
Low Levels

Patients with degenerative diseases present a chronic oxidative stress state, which puts them at a disadvantage when facing viral infections such as COVID-19. This is because there is a close relationship between redox signaling and this inflammatory response. Therefore, chronic changes in the redox balance cause alterations in the regulation of the immune system. An inflammatory response that must be reparative and self-limited loses its function and remains over time. In a chronic state of oxidative stress, there is a deficiency of antioxidants. This results in low levels of hormones, vitamins and trace elements, which are essential for the regulation of these systems. Furthermore, low levels of antioxidants imply a diminished capacity for a regulated inflammatory responses are much more vulnerable to a cytokine storm that mainly attacks the lungs, since they present a vicious circle between the null or diminished response of the antioxidant systems and the loss of regulation of the inflammatory process. Therefore, these patients are at a disadvantage in counteracting the response of defense systems to infection from SAR-COV19. A plausible option may be to restore the levels of Vitamins A, B, C, D, E and of essential trace elements such as manganese, selenium, zinc, in the body, which are key to either preventing or reducing the severity of the response of the immune system to the disease caused by SAR-CoV2. For the present review, we searched the specific sites of the Cochrane library database, PubMed and Medscape. The inclusion criteria were documents written in English or Spanish, published during the last 10 years.

scholarly journals CD28 Deficiency Ameliorates Blast Exposure-Induced Lung Inflammation, Oxidative Stress, Apoptosis, and T Cell Accumulation in the Lungs via the PI3K/Akt/FoxO1 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Yunen Liu ◽  
Changci Tong ◽  
Ying Xu ◽  
Peifang Cong ◽  
Ying Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Weight Ratio ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Lung Weight ◽  
Tissue Samples ◽  
Blast Exposure

Although CD28 is associated with the expression of inflammatory mediators, apoptosis-related protein, immunosuppression, and tumorigenesis, the effects of CD28 deficiency on blast exposure-induced lung injury have not been investigated. In this study, we have explored the effects of CD28 on blast exposure-induced lung injury and studied its potential molecular mechanisms. A mouse model of blast exposure-induced acute lung injury was established. Sixty C57BL/6 wild-type (WT) and CD28 knockout (CD28-/-) mice were randomly divided into control or model groups. Lung tissue samples were collected 24 h and 48 h after blast injury. Histopathological changes and the expressions of inflammatory-related proteins were detected by hematoxylin-eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis and oxidative stress were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS). Inflammation, apoptosis, oxidative stress, and related pathway protein expression were studied by western blotting. In addition, the levels of CD3 and CD28 proteins were measured by flow cytometry. In the current study, we found that CD28 deficiency significantly inhibited blast exposure-induced increases in the lung weight/body weight ratio and wet weight/dry weight ratio; decreased the infiltration of CD44+ leukocytes, CD163+ macrophages, and CD3+ T cells into the lungs; reduced the expressions of proinflammatory cytokines including IL-1β, TNF-α, and IL-6; and markedly increased IL-10 expression. CD28 deficiency also significantly attenuated blast exposure-induced ROS, MDA5, and IREα expressions; increased SOD-1 expression; lowered the number of apoptotic cells and Bax, Caspase-3, and active Caspase-8 expressions; and increased Bcl-2 expression. Additionally, CD28 deficiency significantly ameliorated blast exposure-induced increases of p-PI3K and p-Akt and ameliorated the decrease in the p-FoxO1 expression. Our results suggest that CD28 deficiency has a protective effect on blast exposure-induced lung injury, which might be associated with the PI3K/Akt/FoxO1 signaling pathway.

scholarly journals Pharmacological activation of GPR55 improved cognitive impairment, neuroinflammation, oxidative stress and apoptosis induced by lipopolysaccharide in mice

2020 ◽  
Author(s):  
Xin Wang ◽  
Xiao Tong Xiang ◽  
Jie Hu ◽  
Yu Mei Wu ◽  
YueYue Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Inflammatory Cytokines ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Tunel Staining ◽  
Sod Activity ◽  
Neuroprotective Effects ◽  
Impaired Performance ◽  
Pro Inflammatory Cytokines

Abstract BackgroundNeuroinflammation, oxidative stress and apoptosis are implicated in the pathogenesis of Alzheimer’s disease (AD). The purpose of the present study was to investigate the neuroprotective effects and possible mechanism of G-protein coupled receptor 55 (GPR55) agonist, O-1602, on lipopolysaccharide (LPS)-induced cognitive deficits in mice. MethodsICR mice were treated with intracerebroventricular (i.c.v.) injection of LPS. Cognitive tests were performed, including the open field, Morris water maze, novel object recognition, and passive avoidance tests. The expression of GPR55, NF-κB p65, caspase-3, Bax and Bcl-2 were examined in the hippocampus by western blotting. Pro-inflammatory cytokines and microglia were detected by ELISA kit and immunohistochemical analyses, respectively. The malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity were examined by assay kits. Furthermore, TUNEL-staining was used to detect neuronal apoptosis.ResultsI.c.v. injection of LPS exhibited impaired performance in the behavior tests, which were ameliorated by O-1602 treatment(2.0 or 4.0 μg/mouse, i.c.v.). Importantly, O-1602 reversed GPR55 down-regulation, decreased the expression of NF-κB p65, and suppressed the accumulation of pro-inflammatory cytokines and microglia activation, decreased malondialdehyde (MDA) level, and increased superoxide dismutase (SOD) activity. In addition, O-1602 also significantly decreased Bax and increased Bcl-2 expression as well as decreased caspase-3 activity and TUNEL-positive cells, suppressed neuronal apoptosis in the hippocampus of LPS-treated mice.Conclusionswe conclude that O-1602 may ameliorate LPS-induced cognition deficits via inhibiting neuroinflammation, oxidative stress and apoptosis mediated by NF-κB signaling in mice.

scholarly journals The anti-apoptotic, antioxidant and anti-inflammatory effects of curcumin on acrylamide-induced neurotoxicity in rats

2019 ◽  
Author(s):  
Jie Guo ◽  
Xiaolu Cao ◽  
Xianmin Hu ◽  
Shulan Li ◽  
Jun Wang
Keyword(s):  
Oxidative Stress ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Control Group ◽  
Tunel Staining ◽  
High Dose ◽  
Sprague Dawley ◽  
Curcumin Treatment ◽  
Concurrent Administration ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background: As a chemical extensively used in industrial areas as well as formed during heating of carbohydrate-rich food and tobacco, acrylamide (ACR) has been known as well-established neurotoxic pollutant. Although the precise mechanism is unclear, enhanced apoptosis, oxidative stress and inflammation have been demonstrated to contribute to the ACR-induced neurotoxicity. In this study, we assessed the possible anti-apoptotic, antioxidant and anti-inflammatory effects of curcumin, the most active component in a popular spice known as turmeric, on the neurotoxicity caused by ACR in rats. Methods: Curcumin at the dose of 50 and 100 mg/kg was orally given to ACR- intoxicated Sprague-Dawley rats exposed by ACR at 40mg/kg for 4 weeks. All rats were subjected to behavioral analysis. The HE staining and terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) staining were used to detect histopathological changes and apoptotic cells, respectively. The mRNA and protein expressions of apoptosis-related molecule telomerase reverse transcriptase (TERT) were detected using real-time PCR and immunohistochemistry, respectively. The contents of malondialdehyde (MDA) and glutathione (GSH) as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured as the indicators for evaluating the level of oxidative stress in brain. The levels of pro-inflammatory cytokinestumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in cerebral homogenates were detected using ELISA assay. Results: Concurrent administration of curcumin at the oral doses of 50 and 100 mg/kg with ACR significantly protected the rats from ACR-induced weigh loss and motor function deficits, and improved the pathological alterations in the ACR-intoxicated brains. Curcumin treatment especially at a high dose enhanced the TERT mRNA expression level and increased the number of TERT-positive nerve cells in cortex tissues of ACR intoxicated rats. The levels of MDA, TNF-α and IL-1β in the cerebral homogenates were reduced, the contents of GSH as well as the activities of SOD and GSH-Px were increased by curcumin treatment, compared to ACR control group. Conclusions: These data suggested the anti-apoptotic, antioxidant and anti-inflammatory effects of curcumin on ACR-induced neurotoxicity in rats. And maintaining TERT-related anti-apoptotic function might be one mechanism underlying the protective effect of curcumin on ACR-intoxicated brains.

Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes KKAy mice

2012 ◽  
Vol 302 (1) ◽  
pp. E77-E86 ◽  
Author(s):  
Soichiro Tajima ◽  
Yasumasa Ikeda ◽  
Kaori Sawada ◽  
Noriko Yamano ◽  
Yuya Horinouchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Inflammatory Cytokines ◽  
Iron Reduction ◽  
Iron Concentration ◽  
The Body ◽  
Macrophage Infiltration ◽  
Iron Storage ◽  
Kkay Mice

Iron is an essential trace metal for most organisms. However, excess iron causes oxidative stress through production of highly toxic hydroxyl radicals via the Fenton/Haber-Weiss reaction. Iron storage in the body is reported to be associated with fat accumulation and type 2 diabetes mellitus. We investigated the role of iron in adiposity by using KKAy mice and obese and diabetic model mice. Eight-week-old KKAy mice were divided into two groups and treated with deferoxamine (DFO), an iron chelator agent, or a vehicle for 2 wk. DFO treatment diminished fat iron concentration and serum ferritin levels in KKAy mice. Fat weight and adipocyte size were reduced significantly in DFO-treated mice compared with vehicle-treated mice. Macrophage infiltration into fat was also decreased in DFO-treated mice compared with vehicle-treated mice. Superoxide production and NADPH oxidase activity in fat, as well as urinary 8-hydroxy-2′-deoxyguanosine excretion, were decreased in KKAy mice after DFO treatment while p22phox expression in adipose tissue was diminished in such mice. Ferritin expression in the fat of DFO-treated KKAy mice was decreased. In addition, F4/80-positive cells also presented through both p22phox and ferritin expression. The mRNA expression levels of inflammatory cytokines were also reduced in fat tissue of DFO-treated mice. These findings suggest that reduction of iron levels ameliorates adipocyte hypertrophy via suppression of oxidative stress, inflammatory cytokines, and macrophage infiltration, thereby breaking a vicious cycle in obesity.

scholarly journals MiR-203-3p inhibits the oxidative stress, inflammatory responses and apoptosis of mice podocytes induced by high glucose through regulating Sema3A expression

2020 ◽  
Vol 15 (1) ◽  
pp. 939-950
Author(s):  
Jingfu Chen ◽  
Qing Xu ◽  
Wei Zhang ◽  
YuLan Zhen ◽  
Fei Cheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Cytokines ◽  
High Glucose ◽  
Renal Injury ◽  
Inflammatory Responses ◽  
Cell Model ◽  
The Body ◽  
Enzyme Linked Immunosorbent Assay ◽  
Podocyte Injury

AbstractDiabetic nephropathy (DN) is the most serious long-term microvascular complication of diabetes, which mainly causes podocyte injury. Many studies have shown that microRNAs play a vital role in the development of DN. Studies have shown that miR-203-3p is involved in mesangial cell proliferation and apoptosis of DN mice. Therefore, we speculated that miR-203-3p might be related to the development of DN, but our study does not provide any evidence. In animal experiments, diabetic mice (db/db) were transfected with iR-203-3p overexpression lentiviral vectors (LV-miR-203-3p) and their control (LV-miR-con), with normal mice (db/m) being used as the control. High glucose (HG)-induced podocytes were used to construct a DN cell model in vitro. The expression levels of miR-203-3p, Semaphorin 3A (Sema3A) and inflammatory cytokines were detected by quantitative real-time polymerase chain reaction. Also, serum creatinine and blood urea nitrogen levels were used to evaluate the degree of renal injury in DN mice. Sema3A and apoptosis-related protein levels were assessed by the western blot analysis. Enzyme-linked immunosorbent assay was used to determine the different oxidative stress-related indicators and inflammatory cytokines. Flow cytometry and caspase-3 activity detection were used to analyze the degree of podocyte apoptosis. Our results suggested that the expression of miR-203-3p was lower in DN mice and in HG-induced podocytes. Overexpression of miR-203-3p reduced the body weight, blood glucose and renal injury of DN mice in vivo, as well as relieve the oxidative stress, inflammatory response and apoptosis of HG-induced podocytes in vitro. Functionally, Sema3A was a target of miR-203-3p, and Sema3A overexpression reversed the inhibitory effect of miR-203-3p on HG-induced podocyte injury. Our findings revealed that miR-203-3p alleviated the podocyte injury induced by HG via regulating Sema3A expression, suggesting that miR-203-3p might be a new therapeutic target to improve the progression of DN.

scholarly journals Curcumin Inhibits the PERK-eIF2α-CHOP Pathway through Promoting SIRT1 Expression in Oxidative Stress-induced Rat Chondrocytes and Ameliorates Osteoarthritis Progression in a Rat Model

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Kai Feng ◽  
Yuwei Ge ◽  
Zhaoxun Chen ◽  
Xiaodong Li ◽  
Zhiqing Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Cruciate Ligament ◽  
Immunohistochemical Analysis ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Chondrocyte Apoptosis ◽  
Tunel Staining ◽  
Dependent Manner ◽  
Activating Transcription Factor 4

Oxidative stress plays a crucial role in the occurrence and development of osteoarthritis (OA) through the activation of endoplasmic reticulum (ER) stress. Curcumin is a polyphenolic compound with significant antioxidant and anti-inflammatory activity among various diseases. To elucidate the role of curcumin in oxidative stress-induced chondrocyte apoptosis, this study investigated the effect of curcumin on ER stress-related apoptosis and its potential mechanism in oxidative stress-induced rat chondrocytes. The results of flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining showed that curcumin can significantly attenuate ER stress-associated apoptosis. Curcumin inhibited the expression of cleaved caspase3, cleaved poly (ADP-ribose) polymerase (PARP), C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the chondroprotective protein Bcl2 in TBHP-treated chondrocytes. In addition, curcumin promoted the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4), the ratio of p-PERK/PERK, p-eIF2α/eIF2α. Our anterior cruciate ligament transection (ACLT) rat OA model research demonstrated that curcumin (50 mg/kg and 150 mg/kg) ameliorated the degeneration of articular cartilage and inhibited chondrocyte apoptosis in ACLT rats in a dose-dependent manner. By applying immunohistochemical analysis, we found that curcumin enhanced the expression of SIRT1 and inhibited the expression of CHOP and cleaved caspase3 in ACLT rats. Taken together, our present findings firstly indicate that curcumin could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in tert-Butyl hydroperoxide- (TBHP-) treated rat chondrocytes and ameliorated osteoarthritis development in vivo.

scholarly journals Cardiac Protective Effect of Kirenol against Doxorubicin-Induced Cardiac Hypertrophy in H9c2 Cells through Nrf2 Signaling via PI3K/AKT Pathways

2021 ◽  
Vol 22 (6) ◽  
pp. 3269
Author(s):  
Abdullah M. Alzahrani ◽  
Peramaiyan Rajendran ◽  
Vishnu Priya Veeraraghavan ◽  
Hamza Hanieh
Keyword(s):  
Oxidative Stress ◽  
Biologically Active ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Cardiac Damage ◽  
Stress Markers ◽  
Nrf2 Signaling Pathway ◽  
Study Results

Kirenol (KRL) is a biologically active substance extracted from Herba Siegesbeckiae. This natural type of diterpenoid has been widely adopted for its important anti-inflammatory and anti-rheumatic properties. Despite several studies claiming the benefits of KRL, its cardiac effects have not yet been clarified. Cardiotoxicity remains a key concern associated with the long-term administration of doxorubicin (DOX). The generation of reactive oxygen species (ROS) causes oxidative stress, significantly contributing to DOX-induced cardiac damage. The purpose of the current study is to investigate the cardio-protective effects of KRL against apoptosis in H9c2 cells induced by DOX. The analysis of cellular apoptosis was performed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining assay and measuring the modulation in the expression levels of proteins involved in apoptosis and Nrf2 signaling, the oxidative stress markers. Furthermore, Western blotting was used to determine cell survival. KRL treatment, with Nrf2 upregulation and activation, accompanied by activation of PI3K/AKT, could prevent the administration of DOX to induce cardiac oxidative stress, remodeling, and other effects. Additionally, the diterpenoid enhanced the activation of Bcl2 and Bcl-xL, while suppressing apoptosis marker proteins. As a result, KRL is considered a potential agent against hypertrophy resulting from cardiac deterioration. The study results show that KRL not only activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling pathway, but also suppresses caspase-dependent apoptosis.

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