Eleutheroside E Attenuates Doxorubicin-Induced Cardiotoxicity by Suppressing Ferroptosis Through Activation of the Nrf2/SLC7A11/GPX4 Signaling Pathway.

Rheumatoid arthritis is the most common arthritis and is mainly characterized by symmetric polyarticular joint disorders. Eleutheroside E (EE), a principal active constituent of Acanthopanax senticosus, is reported to have anti-inflammatory effect by inhibiting NF-κB activities. However, the effects of EE on rheumatoid arthritis (RA) severity are largely unknown. The purpose of this study was to indicate whether EE could ameliorate arthritis and reduce inflammatory cytokine release in collagen-induced arthritis (CIA) mice. The results showed that EE attenuated the severity of arthritis by reducing the mean arthritis score and arthritis incidence. EE also significantly decreased the inflammatory cell infiltration, pannus formation, cartilage damage, and bone erosion of CIA mice. Furthermore, EE caused a marked decrease of the production of TNF-α and IL-6 in vivo and in vitro. These observations identify a novel function of EE that results in inhibition of cytokine release, highlighting EE was a potential therapeutic agent for RA.

Cervical cancer (CC) is the common female malignant tumour with non-negligible morbidity and mortality. Eleutheroside E (EE) has anti-oxidative stress, anti-inflammatory and anti-proliferation effects in diverse disease models. However, its anti-tumour role remains unclear. The cell viability, apoptosis rate and protein expressions were detected by CCK-8, flow cytometry and western blot assays, respectively. The metabolic profile was performed by GC/MS analysis. Furthermore, the effect of EE on CC was verified in nude mice. EE notably decreased the viability and increased the cell apoptosis, which could be reversed with 740Y-P treatment. EE treatment changed the metabolic categories of SiHa cells. The fatty acids signalling pathway was the most outstanding differential pathway. Myo-inositol prominently enhanced the level of phosphorylated Akt in a dose-dependent way. Moreover, EE declined the tumour volume and weight and the proliferation, but promoted the apoptosis in vivo. EE reduced the relative expression of phosphorylated PI3K and Akt. However, all these in-vivo results were observably antagonized with myo-inositol treatment. EE plays an anti-tumour role in CC via inhibiting the PI3K pathway and reprogramming the metabolic responses.

There is growing evidence that cognitive dysfunction induced by anesthetics is adversely affecting a large number of elderly surgical patients. Eleutheroside E (EE), a principal component of Eleutherococcus senticosus, exerts obvious protective effects on cognition. The aim of this study was to investigate the neuroprotective effect of EE on isoflurane (ISO)-induced cognitive dysfunction and explore the possible mechanisms. Learning and memory are assessed in novel object recognition and Morris water maze. We found that with ISO exposure, aged rats had a lower preference for the new object and spent less time in the target quarter. However, the amnesia can be alleviated by EE (50 mg/kg, intraperitoneally). Further research focused on the possible protective molecules associated with learning and memory, such as acetylcholine (ACh) and choline acetyltransferase (ChAT), nicotinic acetylcholine receptors (α7-nAChR), and NR2B, is required. The ACh in the hippocampus and serum was decreased after ISO exposure; meanwhile, the expression of ChAT, α7-nAChRs, and NR2B was downregulated. This abnormal state can be reversed by the administration of EE. Here, our results suggested that EE may be a potential therapeutic agent against ISO-induced cognitive dysfunction. The possible mechanism can be attributed to its neuroprotection through enhancing ChAT, which promotes the synthesis of ACh, further influencing the expression of the α7-nAChR-NR2B complex.

Angiotensin IV ameliorates doxorubicin-induced cardiotoxicity by increasing glutathione peroxidase 4 and alleviating ferroptosis

The aim of this study was to investigate the protective effect and mechanism of action (MOA) of Qiliqiangxin capsule (QL) in the deoxycorticosterone acetate (DOCA) salt-induced rat heart failure with preserved ejection fraction (HFpEF) model. Nono-nephrectomy sixty Sprague Dawley (SD) rats received DOCA salt injection and 1% saline in drinking water for 4 weeks and were randomly divided into four groups on average: Model group (n=15), Sac/Val group (Sacubitril Valsartan 0.02 g/kg, n=15), QL-L group (Qiliqiangxin 0.25 g/kg, n=15) and QL-H group (Qiliqiangxin 1 g/kg, n=15). Another Normal group was set (n=15). Blood pressure, N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac index, echocardiography, and hemodynamics were measured to evaluate heart function. Masson and Wheat germ agglutinin (WGA) staining was performed to observe the fibrosis deposition and the cross-sectional area (CSA) of cardiomyocytes. The concentration levels of the serum cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and IL-10 inflammatory factors, were detected by ELISA; matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), transforming growth factor-β1 (TGF-β1), nuclear factor-κB (NF-κB), Smad homologue 2 (Smad2) and Smad homologue 3 (Smad3) expression were detected by Western-blot. Compared with the Model group, QL treatment significantly ameliorated the heart function in DOCA salt-induced rat HFpEF model, showing a decrease in cardiac index, an increase of the EF and E/A ratio, a reduction in the left ventricular anterior/posterior wall (LVAW/LVPW), in the time contraction of isovolumic diastolic time (IVRT), -dP/dt Max, and Tau, and the decrease of serum NT-ProBNP. Masson and WGA staining indicated that QL inhibited the fibrosis deposition and the myocardial hypertrophy compared with the Model group, which was consistent in reducing the protein expression levels of cardiac remodeling such as TGF-β1, MMP2, MMP9, Smad2, and Smad3. Moreover, QL treatment inhibited the expression of NF-κB in the heart tissues and decreased the serum concentration of pro-inflammatory cytokines TNF-α and IL-2, instead, increasing the IL-10 concentration. QL improved the cardiac function and inhibited the myocardial fibrosis in DOCA salt-induced rat HFpEF by improving diastolic dysfunction, preventing left ventricular hypertrophy, and ameliorating the inflammatory responses model in DOCA salt-induced rat HFpEF model.

Effect and mechanism of Qing Gan Zi Shen decoction on heart damage induced by obesity and hypertension

SLAMF9 aggravates myocardial ischemia reperfusion injury through activating the hippo-yap pathway.

Gentianella acuta improves TAC-induced cardiac remodelling by regulating the Notch and PI3K/Akt/FOXO1/3 pathways

Heart failure (HF) is a major cause of morbidity and mortality, and current therapies do not fully prevent adverse remodeling. Traditional Chinese medicine (TCM) formulas are increasingly explored as adjunctive strategies for HF; however, their efficacy and mechanisms require further validation. This study investigated whether Jinxinkang granule (JXK), a clinically used TCM formula, protects against pressure overload-induced HF in mice, and further explored the molecular mechanisms underlying its cardioprotective effects. Pressure overload HF was induced by transverse aortic constriction (TAC) in male C57BL/6J mice. Animals were randomized into control, model, JXK (low, medium, high dose), or positive control (trimetazidine) groups. Cardiac function was assessed by echocardiography, serum biomarkers (NT-proBNP, CK-MB, cTnT) were measured, and cardiac remodeling was assessed by hematoxylin and eosin staining, Masson's trichrome staining, wheat germ agglutinin staining, and TUNEL assay. Expression of senescence markers (p16, p53, MMP3) and cGAS-STING pathway components was analyzed by qPCR, Western blotting, and immunofluorescence. TAC induced systolic dysfunction, ventricular dilation, cardiomyocyte hypertrophy, fibrosis, and increased apoptosis, accompanied by activation of senescence markers and of cGAS-STING signaling. JXK dose-dependently improved left ventricular ejection fraction and fractional shortening, reduced serum injury biomarkers, attenuated cardiomyocyte hypertrophy and fibrosis, and decreased TUNEL-positive cells. Mechanistically, JXK suppressed TAC-induced upregulation of p16, p53, and MMP3, and inhibited cGAS, STING, p-TBK1, and p-IRF3 activation. JXK preserves cardiac function and attenuates remodeling in pressure overload-induced HF, potentially through inhibition of myocardial senescence and suppression of the cGAS-STING pathway.

Doxorubicin is a widely used chemotherapy drug, but its clinical application is limited by dose-dependent cardiotoxicity, known as doxorubicin-induced cardiomyopathy (DIC), for which no specific therapies currently exist. Vericiguat, a soluble guanylate cyclase agonist, has shown significant cardiovascular protective effects. However, its role and the underlying molecular mechanisms in DIC remain unclear. We established both invivo and invitro models of DIC. In the invivo experiments, cardiac function in male wild-type C57BL/6 mice was evaluated through echocardiography, measurement of serum CK-MB and cTnT, and histological examinations. For the invitro studies, cardiomyocyte viability was assessed by CCK-8 assay and PI/Hoechst staining. To evaluate ferroptosis, the accumulation levels of iron, reactive oxygen species (ROS), and lipid peroxides in cardiomyocytes were assessed using FerroOrange staining, DCFH-DA fluorescent probe, and MDA content measurement, respectively. The expression levels of ferroptosis-related markers SLC7A11 and GPX4 were examined by Western blot. Vericiguat significantly alleviated cardiac injury induced by doxorubicin by lowering oxidative stress and inhibiting ferroptosis and directly counteracted cardiomyocyte injury induced by the ferroptosis activator erastin. These findings indicate that vericiguat protects against doxorubicin-induced myocardial ferroptosis, positioning it as a promising therapeutic candidate for DIC and a novel ferroptosis inhibitor.

Background and AimsCirrhotic cardiomyopathy (CCM) is a significant complication of cirrhosis, but its progression and underlying mechanisms remain incompletely understood. This study aimed to investigate dynamic changes in cardiac function, pathology, inflammation, and mitochondrial damage in a mouse model of CCM, and to compare echocardiographic characteristics in patients with cirrhosis.MethodsBile duct ligation was performed in male C57BL/6J mice to induce cirrhosis. Longitudinal analyses were conducted over eight weeks. Cardiac function was assessed using serum biomarkers, echocardiography, and electrocardiography. Pathology was examined with hematoxylin and eosin, Masson’s trichrome, Sirius Red, and wheat germ agglutinin staining. Western blotting and immunohistochemistry were used to detect markers of inflammation, fibrosis, apoptosis, and mitochondrial function. Cardiac and liver function markers were also evaluated in patients with cirrhosis.ResultsMice subjected to bile duct ligation developed progressive cardiac dysfunction, including reduced cardiac output and diastolic dysfunction (end-diastolic interventricular septal thickness, left ventricular internal diameters, stroke volume, and left ventricular end-diastolic volume decreased, whereas ejection fraction and fractional shortening increased), as well as cardiac atrophy. Myocardial apoptosis, inflammation (elevated tumor necrosis factor, interleukin-6, and p65), and fibrosis worsened over time. Mitochondrial injury was characterized by reduced carnitine palmitoyltransferase 1A and peroxisome proliferator-activated receptor alpha, with increased hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase A. In patients with cirrhosis, impaired cardiac function and elevated brain natriuretic peptide levels correlated with total bilirubin.ConclusionsThe progression of CCM is closely associated with cirrhosis severity and appears to be driven by myocardial atrophy, apoptosis, inflammation, fibrosis, and mitochondrial dysfunction.

The human heart can increase its size to supply more blood to the body’s organs. This process, called hypertrophy, can happen during exercise or be caused by medical conditions, such as high blood pressure or inherited genetic diseases. If hypertrophy is continually driven by illness, this can cause the heart to fail and no longer be able to properly pump blood around the body. For hypertrophy to happen, several molecular changes occur in the cells responsible for contracting the heart, including activation of the p38 pathway. Within this pathway is a p38 enzyme as well as a series of other proteins which are sequentially turned on in response to stress, such as inflammatory molecules or mechanical forces that alter the cell’s shape. There are different types of p38 enzyme which have been linked to other diseases, making them a promising target for drug development. However, clinical trials blocking individual members of the p38 family have had disappointing results. An alternative approach is to target other proteins involved in the p38 pathway, such as MKK6, but it is not known what effect this might have. To investigate, Romero-Becerra et al. genetically modified mice to not have any MKK6 protein. As a result, these mice had a shorter lifespan, with hypertrophy developing at a young age that led to heart problems. Romero-Becerra et al. used different mice models to understand why this happened, showing that a lack of MKK6 reduces the activity of a specific member of the p38 family called p38α. However, this blockage boosted a different branch of the pathway which involved two other p38 proteins, p38γ and p38δ. This, in turn, triggered another key pathway called mTOR which also promotes hypertrophy of the heart. These results suggest that drugs blocking MKK6 and p38α could lead to side effects that cause further harm to the heart. A more promising approach for treating hypertrophic heart conditions could be to inhibit p38γ and/or p38δ. However, before this can be fully explored, further work is needed to generate compounds that specifically target these proteins.

Regulated necrosis (necroptosis) plays a pivotal role in the extent of cardiomyocyte loss and the development of post-ischemic adverse remodelling and cardiac dysfunction following myocardial I/R injury. Although HIIT has been reported to give rise to cardioprotection against MI, but the detailed knowledge of its molecular targets for treatment of MI is still not available. The LAD of Male Wistar rats was occluded to induce MI for 30min and reperfusion for eight weeks. We investigated the effect of long-term HIIT for eight weeks on lipid peroxidation, SOD activity and GSH content using ELISA assay. Cardiac function, fibrosis, and infarct size were assessed by echocardiography, Masson's trichrome and Evans Blue/TTC dual staining respectively. The expressions of gene markers of myocardial hypertrophy, fibrosis and key mediators of necroptosis were measured using RT-PCR and western blotting assay respectively. The results indicated that HIIT reduced lipid peroxidation, infarct size and improved endogenous antioxidant system and heart function. Significant decreases in mRNA levels of procollagen α1(I), α1(III), and fibronectin1were observed following HIIT. Moreover, that HIIT significantly decreased the expression of key mediators of necroptosis induced by MI (P< 0.05). There were no significant differences in β-MHC mRNA level in different groups. The findings of study suggest that HIIT might exert cardioprotective effects against post-ischemic adverse remodeling through targeting necroptosis process. Likewise, cardioprotective effects of HIIT in coping with myocardial I/R injury may be associated with RIP1-RIP3-MLKL axis. These findings establish a critical foundation for higher efficiency of exercise-based cardiac rehabilitation post-MI and future research.

Heart failure (HF) is greatly threatening human health and affecting morbidity and mortality worldwide. Troxerutin can alleviate myocardial injury induced by ischemia and hypoxia. The present study aimed to investigate the protective effect of troxerutin on H2 O2 -induced cardiomyocytes and the underlying molecular mechanism. Primary mouse cardiomyocytes morphology induced by H2 O2 in a different duration time was observed by a microscope. After indicated treatment, the viability and apoptosis of cardiomyocytes were detected by CCK-8 assay and flow cytometry analysis. The expression of inflammatory factors and oxidative stress biomarkers was detected by Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and assay kits. Hypoxia inducible factor-1a (HIF-1α) expression was determined by western blot analysis, RT-qPCR analysis and immunofluorescence staining. The apoptosis-related protein expression and the phosphorylation level of janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) were detected by the western blot analysis. As a result, after the H2 O2 treatment in a different duration time, the primary mouse cardiomyocytes gradually stopped beating and the morphology of cardiomyocytes treated with H2 O2 was changed significantly from fusiform shape to round shape. The viability of cardiomyocytes was decreased after H2 O2 induction. The HIF-1α expression was increased after the H2 O2 treatment within 30 min while decreased over 30 min. In addition, troxerutin improved viability and suppressed apoptosis, inflammation and oxidative stress of H2 O2 -induced cardiomyocytes, which was reversed by KC7F2 (a HIF-1α inhibitor) or CHZ868 (a JAK inhibitor). To sum up, troxerutin could regulate HIF-1α by activating JAK2/STAT3 signaling to inhibit oxidative stress, inflammation, and apoptosis of cardiomyocytes induced by H2 O2 .

Background:Myocardial infarction (MI) is a major disease burden. Wild-type p53-induced phosphatase 1 (Wip1) has been studied extensively in the context of cancer and the regulation of different types of stem cells, but the role of Wip1 in cardiac adaptation to MI is unknown. We investigated the significance of Wip1 in a mouse model of MI.Methods:The study began in June 2014 and was completed in July 2016. We compared Wip1-knockout (Wip1-KO) mice and wild-type (WT) mice to determine changes in cardiac function and survival in response to MI. The heart weight/body weight (HW/BW) ratio and cardiac function were measured before MI. Mouse MI was established by ligating the left anterior descending (LAD) coronary artery under 1.5% isoflurane anesthesia. After MI, survival of the mice was observed for 4 weeks. Cardiac function was examined by echocardiography. The HW/BW ratio was analyzed, and cardiac hypertrophy was measured by wheat germ agglutinin staining. Hematoxylin and eosin (H&E) staining was used to determine the infarct size. Gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) was assessed by quantitative real-time polymerase chain reaction (qPCR), and the levels of signal transducers and activators of transcription 3 (stat3) and phosphor-stat3 (p-stat3) were also analyzed by Western blotting. Kaplan-Meier survival analysis, log-rank test, unpaired t-test, and one-way analysis of variance (ANOVA) were used for statistical analyses.Results:Wip1-KO mice had a marginally increased HW/BW ratio and slightly impaired cardiac function before LAD ligation. After MI, Wip1-deficient mice exhibited increased mortality (57.14% vs. 29.17%; n = 24 [WT], n = 35 [Wip1-KO], P < 0.05), increased cardiac hypertrophy (HW/BW ratio: 7 days: 7.25 ± 0.36 vs. 5.84 ± 0.18, n = 10, P < 0.01, and 4 weeks: 6.05 ± 0.17 vs. 5.87 ± 0.24, n = 10, P > 0.05; cross-sectional area: 7 days: 311.80 ± 8.29 vs. 268.90 ± 11.15, n = 6, P < 0.05, and 4 weeks: 308.80 ± 11.26 vs. 317.00 ± 13.55, n = 6, P > 0.05), and reduced cardiac function (ejection fraction: 7 days: 29.37 ± 1.38 vs. 34.72 ± 1.81, P < 0.05, and 4 weeks: 19.06 ± 2.07 vs. 26.37 ± 2.95, P < 0.05; fractional shortening: 7 days: 13.72 ± 0.71 vs. 16.50 ± 0.94, P < 0.05, and 4 weeks: 8.79 ± 1.00 vs. 12.48 ± 1.48, P < 0.05; n = 10 [WT], n = 15 [Wip1-KO]). H&E staining revealed a larger infarct size in Wip1-KO mice than in WT mice (34.79% ± 2.44% vs. 19.55% ± 1.48%, n = 6, P < 0.01). The expression of IL-6 and p-stat3 was downregulated in Wip1-KO mice (IL-6: 1.71 ± 0.27 vs. 4.46 ± 0.79, n = 6, P < 0.01; and p-stat3/stat3: 1.15 ± 0.15 vs. 1.97 ± 0.23, n = 6, P < 0.05).Conclusion:The results suggest that Wip1 could protect the heart from MI-induced ischemic injury.