Doxorubicin (DOX) is an anthracycline chemotherapy drug used in the treatment of various types of cancer. However, short-term and long-term cardiotoxicity limits the clinical application of DOX. ...Currently, dexrazoxane is the only approved treatment by the United States Food and Drug Administration to prevent DOX-induced cardiotoxicity. However, a recent study found that pre-treatment with dexrazoxane could not fully improve myocardial toxicity of DOX. Therefore, further targeted cardioprotective prophylaxis and treatment strategies are an urgent requirement for cancer patients receiving DOX treatment to reduce the occurrence of cardiotoxicity. Accumulating evidence manifested that Sirtuin 1 (SIRT1) could play a crucially protective role in heart diseases. Recently, numerous studies have concentrated on the role of SIRT1 in DOX-induced cardiotoxicity, which might be related to the activity and deacetylation of SIRT1 downstream targets. Therefore, the aim of this review was to summarize the recent advances related to the protective effects, mechanisms, and deficiencies in clinical application of SIRT1 in DOX-induced cardiotoxicity. Also, the pharmaceutical preparations that activate SIRT1 and affect DOX-induced cardiotoxicity have been listed in this review.
Although it is known that the expression and activity of sirtuin 1 (SIRT1) significantly decrease in doxorubicin (DOX)-induced cardiomyopathy, the role of interaction between SIRT1 and sestrin 2 ...(SESN2) is largely unknown. In this study, we investigated whether SESN2 could be a crucial target of SIRT1 and the effect of their regulatory interaction and mechanism on DOX-induced cardiac injury. Here, using DOX-treated cardiomyocytes and cardiac-specific Sirt1 knockout mice models, we found SIRT1 deficiency aggravated DOX-induced cardiac structural abnormalities and dysfunction, whereas the activation of SIRT1 by resveratrol (RES) treatment or SIRT1 overexpression possessed cardiac protective effects. Further studies indicated that SIRT1 exerted these beneficial effects by markedly attenuating DOX-induced oxidative damage and apoptosis in a SESN2-dependent manner. Knockdown of Sesn2 impaired RES/SIRT1-mediated protective effects, while upregulation of SESN2 efficiently rescued DOX-induced oxidative damage and apoptosis. Most importantly, SIRT1 activation could reduce DOX-induced SESN2 ubiquitination possibly through reducing the interaction of SESN2 with mouse double minute 2 (MDM2). The recovery of SESN2 stability in DOX-impaired primary cardiomyocytes by SIRT1 was confirmed by Mdm2-siRNA transfection. Taken together, our findings indicate that disrupting the interaction between SESN2 and MDM2 by SIRT1 to reduce the ubiquitination of SESN2 is a novel regulatory mechanism for protecting hearts from DOX-induced cardiotoxicity and suggest that the activation of SIRT1-SESN2 axis has potential as a therapeutic approach to prevent DOX-induced cardiotoxicity.
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•DOX-induced cardiotoxicity is based on decreased SIRT1 and SESN2 levels.•SIRT1 activation improves DOX-induced cardiac oxidative stress and apoptosis.•The benefits of SIRT1 in DOX-impaired cardiac function require the activation of SESN2.•SIRT1 reduces ubiquitination and degradation of SESN2 via MDM2.
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Sestrin2 (Sesn2) is a powerful anti-oxidant that can prevent acute and chronic diseases. The role of Sesn2 has been thoroughly reviewed in liver, nervous system, and immune system ...diseases. However, there is a limited number of reviews that have summarized the effects of Sesn2 in heart and vascular diseases, and very less literature-based information is available on involvement of Sesn2 in renal and respiratory pathologies. This review summarizes the latest research on Sesn2 in multi-organ stress responses, with a particular focus on the protective role of Sesn2 in cardiovascular, respiratory, and renal diseases, emphasizing the potential therapeutic benefit of targeting Sesn2 in stress-related diseases.
Diabetes mellitus (DM) has been one of the largest health concerns of the 21st century due to the serious complications associated with the disease. Therefore, it is essential to investigate the ...pathogenesis of DM and develop novel strategies to reduce the burden of diabetic complications. Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD
)-dependent deacetylase, has been reported to not only deacetylate histones to modulate chromatin function but also deacetylate numerous transcription factors to regulate the expression of target genes, both positively and negatively. SIRT1 also plays a crucial role in regulating histone and DNA methylation through the recruitment of other nuclear enzymes to the chromatin. Furthermore, SIRT1 has been verified as a direct target of many microRNAs (miRNAs). Recently, numerous studies have explored the key roles of SIRT1 and other related epigenetic mechanisms in diabetic complications. Thus, this review aims to present a summary of the rapidly growing field of epigenetic regulatory mechanisms, as well as the epigenetic influence of SIRT1 on the development and progression of diabetic complications, including cardiomyopathy, nephropathy, and retinopathy.
Fibroblast growth factor 1 (FGF1) has a critical regulatory role in the development of the cardiovascular system (CVS) and is strongly associated with the progression or treatment of cardiovascular ...diseases (CVDs). However, the regulatory mechanisms of FGF1 in CVS and CVDs have not yet been fully elucidated. Therefore, this review article summarized the existing literature reports on the role of FGF1 in CVS under physiological and pathological conditions. First, the expression and physiological functions of endogenous FGF1 is fully demonstrated. Then, we analyzed the role of exogenous FGF1 in normal CVS and related pathological processes. Specifically, the potential signaling pathways might be mediated by FGF1 in CVDs treatment is discussed in detail. In addition, the barriers and feasible solutions for the application of FGF1 are further analyzed. Finally, we highlight therapeutic considerations of FGF1 for CVDs in the future. Thus, this article may be as a reference to provide some ideas for the follow-up research.
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A cumulative and progressively developing cardiomyopathy induced by adriamycin (ADR)-based chemotherapy is a major obstacle for its clinical application. However, there is a lack of safe and ...effective method to protect against ADR-induced cardiotoxicity. Here, we found that mRNA and protein levels of FGF1 were decreased in ADR-treated mice, primary cardiomyocytes and H9c2 cells, suggesting the potential effect of FGF1 to protect against ADR-induced cardiotoxicity. Then, we showed that treatment with a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency significantly prevented ADR-induced cardiac dysfunction as well as ADR-associated cardiac inflammation, fibrosis, and hypertrophy. The mechanistic study revealed that apoptosis and oxidative stress, the two vital pathological factors in ADR-induced cardiotoxicity, were largely alleviated by FGF1ΔHBS treatment. Furthermore, the inhibitory effects of FGF1ΔHBS on ADR-induced apoptosis and oxidative stress were regulated by decreasing p53 activity through upregulation of Sirt1-mediated p53 deacetylation and enhancement of murine double minute 2 (MDM2)-mediated p53 ubiquitination. Upregulation of p53 expression or cardiac specific-Sirt1 knockout (Sirt1-CKO) almost completely abolished FGF1ΔHBS-induced protective effects in cardiomyocytes. Based on these findings, we suggest that FGF1ΔHBS may be a potential therapeutic agent against ADR-induced cardiotoxicity.
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•Cardiac expression of FGF1 were decreased by ADR treatment.•FGF1ΔHBS prevented ADR-induced cardiac structural abnormalities and dysfunction.•FGF1ΔHBS inhibited ADR-induced oxidative stress and apoptosis by deacetylating p53.•Deacetylated p53 induced by FGF1ΔHBS accelerated the ubiquitination of p53 by MDM2.
Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential ...antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)-induced obese mice.
The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3β) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-
or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice.
This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2
AKT/GSK-3β/Src family tyrosine kinase signaling pathway.
40, 598-615.
Metanephric adenoma (MA) is a rare type of benign renal epithelial tumor that can develop at any age. Nonetheless, MA is extremely rare in children and only a few cases have been reported to date. ...The present study aimed to report the case of a 5-year-old female found to have a mass in the right kidney during a routine pre-enrollment physical examination. Computed tomography (CT) images revealed multiple high-density calcifications in the mass, and contrast-enhanced CT and magnetic resonance imaging demonstrated that the mass was significantly enhanced in the cortical phase and decreased in the medullary phase. Based on these findings, the mass was initially diagnosed as angiomyolipoma before surgery; however, postoperative pathology confirmed the mass to be a MA. MAs are typically a type of soft tissue mass with relatively uniform density or signal, showing delayed enhancement in contrast-enhanced scanning. However, the mass found in the present study presented diffused high-density calcification, which was obvious in the early phase of contrast-enhanced scanning but weakened in the delayed enhancement phase. In conclusion, the present case study demonstrated that MA should be considered as one of the imaging differential diagnoses of fat-poor angiomyolipoma, renal carcinoma and oncocytoma. Key words: metanephric adenoma, kidney, angiomyolipoma, child, computed tomography
Objective: To investigate the correlation between the DCE-CT imaging biomarkers and histological biomarkers of tumor angiogenesis in adrenal adenomas and non-adenomas for the enhancement mechanism of ...DCE-CT. Methods: Forty-two patients with 45 adrenal masses including 27 adenomas and 18 non-adenomas diagnosed pathologically were enrolled in this study. The features of DCE-CT (imaging biomarkers) and tumor angiogenesis (histological biomarkers) in adrenal masses were evaluated, and their correlations were explored. Results: The enhanced features of DCE-CT in adrenal masses were classified: rapid washout group and slow washout group. Type A and C of time density (TD) curves, relative washout rate (Washr) ≥34%, and absolute washout rate (Washa) ≥43% belonged to the rapid group. In contrast, type B, D and E, Washr <34%, and Washa <43% belonged to the slow group. There was significant difference between the biomarkers of DCE-CT in adrenal masses. The rapid group was mainly found in adenomas, whereas the slow was mainly present in nonadenomas. The tumor angiogenesis, histological biomarkers, including microvessel density (MVD), vascular endothelial growth factor (VEGF), and microvascular ultrastructures demonstrated significant difference between the rapid and the slow washout group revealed by DCE-CT. The MVD and VEGF expression in rapid group were remarkably higher than those in slow group. Meanwhile, the tumor angiogenesis was also significantly different between adenomas and nonadenomas. The MVD and VEGF expression were also significantly higher in adenomas than those in nonadenomas. Furthermore, different microvascular ultrastructures were identified between adenomas and nonadenomas, which were in accordance with those between the rapid and the slow group. Microvascular ultrastructures in adrenal adenomas and/or the rapid group showed regular lumens and nonstenosis; more pinocytotic vesicles and fenestrations of endothelium; widening of the intercellular space; uniform thinning and better integrity of basal membrane; regular and uniform thinning, along with less stroma of extra vessel space. In comparison, opposite microvascular ultrastructures, in adrenal nonadenomas and/or the slow group. Conclusion: The close correlation of DCE-CT imaging biomarkers and histological biomarkers of tumor angiogenesis was found between adrenal adenomas and nonadenomas. Tumor angiogenesis in adrenal adenomas and nonadenomas were shown the different enhancement characteristics at DCE-CT.
Abstract Objective Inflammation is closely linked to pulmonary arterial hypertension (PAH). Salusin-β, a bioactive peptide, has been reported to participate in vascular inflammation. We therefore ...hypothesized that salusin-β contributes to monocrotaline (MCT)-induced PAH in rats. Methods Male Sprague-Dawley rats were treated with MCT (60 mg kg−1 , single intraperitoneal injection). Salusin-β expression in the lungs of the MCT-treated rats was evaluated using immunofluorescence staining, western blot, and real-time PCR. For salusin-β blockade assay, rats injected with MCT were given a chronic infusion of anti-salusin-β immunoglobulin G (IgG) (salusin-β blocker, 1.0 μg kg−1 h−1 ) or isotype-matched control IgG. Four weeks after MCT+anti-salusin-β treatment, the effects of salusin-β blockade were determined using hemodynamics, western blot, real-time PCR, and immunohistochemical detection. The effect of salusin-β on human pulmonary arterial endothelial cell (HPAEC) function was detected by adhesion and tube formation experiments in vitro. Results Salusin-β expression was significantly increased in the lungs of the MCT-treated rats, and immunofluorescence results showed that salusin-β was predominantly expressed in pulmonary macrophages and vascular endothelial cells. Salusin-β blockade significantly ameliorated PAH by acting against pulmonary vascular remodeling, decreasing macrophage infiltration, and reducing pro-inflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity in the lungs of the MCT-treated rats. In addition, salusin-β could induce cell adhesion and accelerate angiogenesis by activating the NF-κB pathway and promoting pro-inflammatory cytokine expression in the cultured HPAECs. This effect was suppressed by addition of the NF-κB inhibitor, N-acetyl-L-cysteine. Conclusions Salusin-β plays a crucial role in the development of MCT-induced PAH models.
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