Ferroptosis and its role in cardiomyopathy Li, Danlei; Pi, Wenhu; Sun, Zhenzhu ...
Biomedicine & pharmacotherapy,
September 2022, 2022-09-00, 20220901, 2022-09-01, Letnik:
153
Journal Article
Recenzirano
Odprti dostop
Heart disease is the leading cause of death worldwide. Cardiomyopathy is a disease characterized by the heart muscle damage, resulting heart in a structurally and functionally change, as well as ...heart failure and sudden cardiac death. The key pathogenic factor of cardiomyopathy is the loss of cardiomyocytes, but the related molecular mechanisms remain unclear. Ferroptosis is a newly discovered regulated form of cell death, characterized by iron accumulation and lipid peroxidation during cell death. Recent studies have shown that ferroptosis plays an important regulatory roles in the occurrence and development of many heart diseases such as myocardial ischemia/reperfusion injury, cardiomyopathy and heart failure. However, the systemic association of ferroptosis and cardiomyopathy remains largely unknown and needs to be elucidated. In this review, we provide an overview of the molecular mechanisms of ferroptosis and its role in individual cardiomyopathies, highlight that targeting ferroptosis maybe a potential therapeutic strategy for cardiomyopathy therapy in the future.
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•Ferroptosis plays pivotal roles in both primary and secondary cardiomyopathies.•Different regulation pathways mediate ferroptosis in various cardiomyopathies.•Targeting ferroptosis can be a potential therapeutic strategy in cardiomyopathy therapy.
Doxorubicin (DOX) is an anthracycline antibiotic that is used extensively for the management of carcinoma; however, its clinical application is limited due to its serious cardiotoxic side effects. ...Ferroptosis represents iron-dependent and reactive oxygen species (ROS)-related cell death and has been proven to contribute to the progression of DOX-induced cardiomyopathy. Fisetin is a natural flavonoid that is abundantly present in fruits and vegetables. It has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity in experimental rats. However, the underlying mechanisms remain unknown. The present study investigated the cardioprotective role of fisetin and the underlying molecular mechanism through experiments in the DOX-induced cardiomyopathy rat and H9c2 cell models. The results revealed that fisetin treatment could markedly abate DOX-induced cardiotoxicity by alleviating cardiac dysfunction, ameliorating myocardial fibrosis, mitigating cardiac hypertrophy in rats, and attenuating ferroptosis of cardiomyocytes by reversing the decline in the GPX4 level. Mechanistically, fisetin exerted its antioxidant effect by reducing the MDA and lipid ROS levels and increasing the glutathione (GSH) level. Moreover, fisetin exerted its protective effect by increasing the SIRT1 expression and the Nrf2 mRNA and protein levels and its nuclear translocation, which resulted in the activation of its downstream genes such as
and
. Selective inhibition of SIRT1 attenuated the protective effects of fisetin in the H9c2 cells, which in turn decreased the GSH and GPX4 levels, as well as
,
, and
expressions. In conclusion, fisetin exerts its therapeutic effects against DOX-induced cardiomyopathy by inhibiting ferroptosis
SIRT1/Nrf2 signaling pathway activation.
•Dietary 1.00 g/kg dandelion extract (DE) supplementation significantly increased weight gain rate of golden pompano.•Dietary DE improved intestinal morphology of golden pompano.•Dietary DE improved ...intestinal microbiota of golden pompano.
The gut microbiota plays an important role in growth performance, intestinal mucosal barrier, digestion and absorption of nutrients and immune responses. In this study, we investigated the effect of dietary dandelion extract (DE) on growth performance, expression of immune related genes in the spleen, intestinal morphology and microbiota of golden pompano (Trachinotus ovatus). Golden pompanos were fed three diets adding 0 (DE0), 0.50 (DE1), 1.00 (DE2) g/kg DE for 8 weeks. At the end of this trial, dietary 1.00 g/kg DE supplementation significantly increased weight gain rate and feed intake compared to those of the control group (P < 0.05). Meanwhile, dietary 1.00 g/kg DE supplementation significantly up-regulated transcription levels of glutathione peroxidase and interleukin 10 in the spleen of fish. However, dietary DE supplementation had no significant effect on transforming growth factor β1, glutathione reductase and catalase in the spleen of fish. Moreover, dietary 0.50–1.00 g/kg DE supplementation improved the richness and diversity of gut microbiota, increase the relative abundance of Actinobacteria and Firmicutes, and reduce the proportion of harmful microbial taxa. Furthermore, dietary DE improved intestinal morphology and immunity by increasing intestinal goblet cells numbers and decreasing epithelial lymphocyte numbers. In conclusion, dietary 1.00 g/kg DE supplementation was clearly beneficial for golden pompano by improving growth performance, gut morphology and microbiota and it could use as a functional feed additive in aquaculture.
Purpose
The pro-aging miRNA, miR-34a, is hyperactivated in the cardiac myocardial tissues of patients and mice with diabetes, leading to diabetic cardiomyopathy (DCM). Increasing evidence suggests ...that dihydromyricetin (DHM) can be used to effectively treat cardiomyopathy. In this study, we investigated whether DHM affects the expression of miR-34a in DCM.
Methods
The expression of miR-34a in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice was determined by microRNA isolation and quantitative reverse transcription-polymerase chain reaction. Lipofectamine 3000 was used to transfect cardiomyocytes with miR-34a inhibitor, miR-34a mimics, and miR-control. These agents were intravenously injected into the tail vein of streptozotocin-induced diabetic mice. Autophagy and apoptosis were assessed in high-glucose-induced cardiomyocytes and cardiac tissue in diabetic mice by western blotting, immunofluorescence, Masson staining, hematoxylin and eosin staining (H&E), and electron microscopy.
Results
DHM clearly ameliorated the cardiac dysfunction in the diabetic mice. The expression of miR-34a was up-regulated in high-glucose-induced cardiomyocytes and in the hearts of diabetic mice, thus impairing autophagy. Treatment with DHM decreased the expression of miR-34a and rescued the impairment of autophagy in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice, while the miR-34a mimic offset the effect of DHM with respect to the development of DCM by inhibiting autophagy.
Conclusions
By decreasing the expression of miR-34a, DHM restores impaired autophagy, and thus ameliorates DCM. Therefore, DHM may potentially be used in the treatment of DCM.
Summary
Background
Epidemiological data of coeliac disease are lacking from the central Asian region.
Aims
To verify the occurrence of coeliac disease amongst four major ethnic groups of Xinjiang ...Uyghur Autonomus Region, China.
Methods
2277 in‐patients with gastrointestinal symptoms (1391 Han, 608 Uyghur, 146 Kazakh and 132 Hui; mean age: 54 ± 12.8 years) were included. Total IgA, anti‐deamidated gliadin peptide (DGP)‐IgG, and anti‐tissue transglutaminase (anti‐tTG)‐IgA were analysed. All antibody‐positive subjects were further tested for endomysial (EMA) antibodies and were HLA genotyped. All subjects with antibody positivity were asked to undergo intestinal biopsy. In addition, a subset of antibody‐negative subjects were tested for HLA‐DQA1and DQB1.
Results
Among the 2277 subjects, 29 subjects were defined as coeliac disease autoimmune (positive results for anti‐tTG IgA and EMA‐IgA) (1.27%; 95% confidence interval, 0.81%‐1.73%), eight of them underwent biopsy and all showed coeliac disease histology (0.35%; 95% Cl, 0.11%‐0.59%). The frequency of coeliac disease autoimmunity was lowest among the Han (0.79%), followed by the Uyghur (1.81%), the Kazakh (2.05%) and the Hui (3.03%). The frequency of the HLA‐DQ2 and/or DQ8 haplotype was highest in the Uyghur (52.1%), followed by the Hui (44.4%), the Kazakh (40.0%) and the Han (39.4%). Besides, a three times higher frequency of coeliac disease autoimmunity was found among rural living subjects with significantly higher wheat consumption compared to urban living subjects (3.16% vs 0.97%, P < 0.01).
Conclusions
In Xinjiang, coeliac disease does occur, especially in the rural area. The HLA haplotype and environment play key roles in the development of coeliac disease.
Myocardial contractile dysfunction in diabetic cardiomyocytes is a significant promoter of heart failure. Herein, we investigated the effect of icariin, a flavonoid monomer isolated from
, on ...diabetic cardiomyopathy (DCM) and explored the mechanisms underlying its unique pharmacological cardioprotective functions. High glucose (HG) conditions were simulated
using cardiomyocytes isolated from neonatal C57 mice, while DCM was stimulated
in db/db mice. Mice and cardiomyocytes were treated with icariin, with or without overexpression or silencing of Apelin and Sirt3
transfection with adenoviral vectors (Ad-RNA) and specific small hairpin RNAs (Ad-sh-RNA), respectively. Icariin markedly improved mitochondrial function both
and
, as evidenced by an increased level of mitochondrial-related proteins
western blot analysis (PGC-1α, Mfn2, and Cyt-b) and an increased mitochondrial membrane potential, as observed
JC-1 staining. Further, icariin treatment decreased cardiac fibrogenesis (Masson staining), and inhibited apoptosis (TUNEL staining). Together, these changes improved cardiac function, according to multiple transthoracic echocardiography parameters, including LVEF, LVSF, LVESD, and LVEDD. Moreover, icariin significantly activated Apelin and Sirt3, which were inhibited by HG and DCM. Importantly, when Ad-sh-Apelin and Ad-sh-Sirt3 were transfected in cardiomyocytes or injected into the heart of db/db mice, the cardioprotective effects of icariin were abolished and mitochondrial homeostasis was disrupted. Further, it was postulated that since Ad-Apelin induced different results following increased Sirt3 expression, icariin may have attenuated DCM development by preventing mitochondrial dysfunction through the Apelin/Sirt3 pathway. Hence, protection against mitochondrial dysfunction using icariin may prove to be a promising therapeutic strategy against DCM in diabetes.
•Doxorubicin induces acute cardiotoxicity accompanied by disordered apoptosis and autophagy in vivo and vitro.•Fucoidan could restore doxorubicin-induced acute cardiotoxicity by inhibiting apoptosis ...and promoting autophagy.•The protective role of fucoidan can be impaired by inhibiting the activation of the JAK2/STAT3 pathway.
Doxorubicin (DOX) is well-known for its potent antitumor activity but limited by its multiple and serious adverse effects. A major adverse effect is acute cardiotoxicity; yet, its mechanism has not been elucidated. Fucoidan is a multifunctional and nontoxic polysaccharide that is widely studied because of its favorable biological activities and safety. Hence, we proposed that fucoidan may play a protective role in DOX-induced acute cardiotoxicity without causing additional side effects. Sprague-Dawley rats were injected intraperitoneally with a single high dose of DOX to induce acute cardiac injury. Fucoidan was administered orally before DOX injection and AG490, a JAK2 inhibitor, was applied to verify the participation of the JAK2/STAT3 pathway. In vitro, H9C2 cells were treated with the same drugs at different concentrations and intervention times. in vivo and in vitro results demonstrated that DOX administration induced myocardial damage accompanied by acceleratory apoptosis and deficient autophagy in heart tissues or cells, which could be significantly improved by fucoidan supplement. AG490 partly abolished the cardioprotective effects of fucoidan, suggesting the involvement of JAK2 signaling. Additionally, western blotting revealed DOX-induced JAK2/STAT3 pathway activation, which was enhanced by fucoidan and weaken by AG490. Hence, fucoidan exerted a favorable effect on DOX-induced cardiotoxicity by enhancing autophagy and suppressing apoptosis in a JAK2/STAT3-dependent manner, which may provide a promising and novel therapeutic strategy against negative chemotherapy-induced effects.
Background The differential diagnosis of endometrial stromal tumor (EST) and uterine cellular leiomyoma (CL) remains a challenge in clinical practice, especially low grade endometrial stromal sarcoma ...(ESS) and CL, suggesting the need for novel immunomarkers panels for differential diagnosis. Interferon-induced transmembrane protein 1 (IFITM1) is a novel immunomarker for endometrial stromal cells, h-caldesmon is an immunomarker for smooth muscle cells and has a higher specificity than smooth muscle actin (SMA). So this study aimed to evaluate whether IFITM1, cluster of differentiation 10(CD10), SMA, and h-caldesmon are useful biomarker combinations for the differential diagnosis of EST and CL. Methods Tissue microarrays were used to detect IFITM1, CD10, SMA, and h-caldesmon immunohistochemical staining in 30 EST and 33 CL cases. Results The expressions of IFITM1 and CD10 were high in EST (86.7 and 63.3%, respectively) but low in CL (18.2 and 21.2%), whereas those of h-caldesmon and SMA were high in CL (87.9 and 100%) and low in EST (6.9 and 40%). In diagnosing EST, IFITM1 shows better sensitivity and specificity (86.7 and 81.8%, respectively) than CD10 (63.3 and 78.8%). The specificity of h-caldesmon in diagnosing CL was significantly higher (93.1%) than that of SMA (60%). When all four antibodies were combined for the differential diagnosis, the area-under-the-curve (AUC) predictive value was 0.995. The best combination for diagnosing EST was IFITM1 (+) or CD10 (+) and h-caldesmon (-) (sensitivity 86.7%, specificity 93.9%). Conclusion The best combination for diagnosing CL were h-caldesmon (+) and SMA (+) (sensitivity 87.9%, specificity 100%). IFITM1, CD10, SMA, and h-caldesmon are a good combination for the differential diagnosis of EST and CL. Keywords: IFITM1, CD10, SMA , H-caldesmon, Endometrial stromal tumor, Cellular leiomyoma
Recent studies have revealed that a novel selective sodium-glucose cotransporter 1 (SGLT1) inhibiton has shown beneficial effects in cardiovascular diseases. However, the question of whether SGLT1 ...inhibition influences diabetic cardiomyopathy (DCM) remains unanswered. In this study, we investigated the influence and underlying mechanism of SGLTI inhibition on DCM.
SGLT1 levels were measured in diabetic patients with similar conditions who visited our hospital from January to December 2019. Wistar male rats (n = 50) were divided into five groups: control, diabetes induced by streptozotocin infusion, and diabetes treated with 0.5, 1.0, or 1.5 mg/kg mizagliflozin via stomach gavage for 12 weeks. H9C2 cardiomyocytes were treated with mizagliflozin and then exposed to a high glucose concentration (30 mmol/L). TUNEL assays were performed, and bcl2, bax, p-p38, p-Erk, p-JNK and caspase-3 levels were measured. We used siRNA and an SGLT1 overexpression plasmid to detect the effects of SGLT1.
SGLT1 levels were significantly elevated in DCM patients, and receiver operating characteristic (ROC) curve analysis identified SGLT1 as influencing DCM. The area under the curve (AUC) was 0.705 (
< 0.05), with 65.8% sensitivity, and 62.2% specificity. SGLT1 inhibition appeared to attenuate apoptosis in DCM via the JNK and p38 pathway.
SGLT1 can be used as a marker for the diagnosis of DCM, and SGLT1 inhibition can attenuate apoptosis, thereby suppressing DCM development via the JNK and p38 pathway.
This experiment was conducted to investigate the effects of partial replacement of fish meal with black soldier fly larvae (BSFL) meal on growth performance, body and muscle nutrients, lipid ...metabolism, intestinal morphology and microbiota of juvenile golden pompano (Trachinotus ovatus). Three isolipidic (12.40 ± 0.29%) and isoproteinic (42.98 ± 0.02%) experimental diets were formulated to feed golden pompano by replacing 0% (BSFL0), 25% (BSFL25) and 50% (BSFL50) of fish meal with BSFL meal. The experiment lasted for a total of 8 weeks. The results showed that compared with BSFL0, BSFL25 could significantly increase feed intake of golden pompano (P < 0.05). However, BSFL50 significantly reduced growth performance (P < 0.05). The hepatosomatic index, body and muscle crude fat in BSFL25 and BSFL50 decreased. BSFL25 could significantly reduce the activity of fatty acid synthase (FAS) and significantly enhance the activity of lipase (LPS) (P < 0.05). Both BSFL25 and BSFL50 could significantly reduce the number and volume of lipid droplets in the liver, but BSFL50 could damage the intestinal morphology and shorten the intestinal villi. Compared with BSFL0, the richness (Chao1, ACE, Sobs) and diversity (Shannon and Simpson) of intestinal microbiota in BSFL25 and BSFL50 were increased, and the abundance of Proteobacteria, Actinobacteria and Bacteroidetes was increased. In conclusion, the replacement of 25% fish meal in the feed by BSFL meal improved the food intake, lipid deposition in the liver, and intestinal microbiota balance of golden pompano, and had no harmful effects on growth and intestinal health. However, when the substitution level reached 50%, it would have a negative impact on growth and intestinal health.
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