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Doxorubicin is an effective chemotherapeutic agent prescribed to treat solid tumors (e.g., ovary, breast, and gastrointestinal cancers). This anti-cancer drug has various side effects, such as allergic reactions, cardiac damage, hair loss, bone marrow suppression, vomiting, and bladder irritation. The most dangerous side effect of doxorubicin is cardiomyopathy, leading to congestive heart failure. The exact mechanisms of doxorubicin-induced cardiotoxicity remain incompletely understood. Alteration in myocardial structure and functional cardiac disorders is provoked by doxorubicin administration; subsequently, cardiomyopathy and congestive heart failure can occur. Congestive heart failure due to doxorubicin is associated with mortality and morbidity. Probably, doxorubicin-induced cardiotoxicity starts from myocardial cell injury and is followed by left ventricular dysfunction. Many factors and multiple pathways are responsible for the creation of doxorubicin-induced cardiotoxicity. Inflammatory cytokines, oxidative stress pathways, mitochondrial damage, intracellular Ca2+ overload, iron-free radical production, DNA, and myocyte membrane injuries have critical roles in the pathophysiology of doxorubicin-induced cardiotoxicity. Unfortunately, there are currently a few medications for the treatment of doxorubicin-induced cardiotoxicity in clinical settings. Extensive basic and clinical researches have been carried out to discover preventive treatments. This review briefly discusses the basic and experimental approaches for treating or preventing doxorubicin-mediated cardiotoxicity based on its pathophysiological mechanisms.

Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia–reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.

In vitro sperm preparation/incubation and cryopreservation are associated with oxidative stress as the main cause of sperm damage, and different strategies are used to improve sperm quality in in vitro conditions to treat male infertility. Growth factors (GFs) are biological molecules that play different roles in various cellular processes such as growth, proliferation, and differentiation. Many studies have shown that GFs and their receptors are expressed in the male reproductive system. In vitro supplementation of GFs to improve sperm parameters has yielded useful results. There are many studies on the effects of GFs on sperm quality improvement and subsequent assisted reproductive technology results. Hence, this study will review the in vitro results of various GFs including brain-derived neurotrophic factor, nerve growth factor, fibroblast growth factor, insulin-like growth factor I, and vascular endothelial growth factor to improve sperm quality. Key words: Growth factors, Sperm, ROS, Cryopreservation, In vitro.

Matrix metalloproteinases (MMPs) are a family of enzymes that play an important role in the pathophysiology of hypertensive disorders, particularly through their involvement in extracellular matrix (ECM) remodeling and vascular dysfunction. Their activity is closely linked to hypertension-mediated organ damage, which affects the vascular and cardio-renal systems. MMPs are responsible for degrading various components of the ECM, which is crucial for maintaining vascular structure and function. In hypertensive patients, several MMPs, including MMP-1, MMP-3, and MMP-9, are often found at elevated levels. This is associated with vascular remodeling and dysfunction due to chronic high blood pressure. The activation of MMPs in hypertension can be triggered by several factors, such as oxidative stress, inflammatory cytokines, and vasoactive agents like angiotensin II. In addition to increasing MMP activity, these variables cause an imbalance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), which are the MMPs’ natural inhibitors. This imbalance contributes to excessive degradation of the ECM and promotes pathological changes in vascular smooth muscle cells (VSMCs), leading to their transition from a contractile to a synthetic phenotype. This shift facilitates cell growth and migration, exacerbating vascular remodeling. Given their critical roles in hypertension-related organ damage, MMPs are being explored as potential pharmacological targets. Inhibitors of MMPs may help mitigate the adverse effects of hypertension by restoring balance in ECM remodeling processes. Understanding their mechanisms opens avenues for targeted therapies that could significantly improve outcomes for individuals suffering from hypertension-related complications.

Chemotherapy is one of the routine treatment for preventing rapid growth of the tumor cells. However, chemotherapeutic agents, especially doxorubicin cause damages to the normal cells especially cardiomyocytes. Cardiotoxicity induced by chemotherapeutic drugs lead to the myocardial cell injury and finally causes left ventricular dysfunction. It seems that there were some differences in the severity of cardiovascular side effects of drugs used in the treatment of cancers. Sex hormones in male and female play crucial roles in cardiovascular development and physiological function of the heart and blood vessels. Gender differences and sex-specific hormones influence various aspects of cardiovascular health, including ventricular function, mitochondrial autophagy, and the development of abdominal aortic aneurysms. The most important gender related hormones are LH, FSH, testosterone, estrogen, progesterone, prolactin and oxytocin. They exert very important cardiovascular effects via different signaling mechanisms. Sex related hormones are also important in the cardiovascular side effects of chemotherapeutic agents, so that chronic cardiotoxicity induced by anthracyclines is more common in women. During different stages of life (before, during, and after sexual life), the levels of these hormones will be changed. This alterations can affect cardiovascular function during physiological conditions and pathological process. Because of the importance of the sex related hormones in the cardiac function, in this review we tried to comprehensively elucidate the role of these physiological hormones in cardiotoxicity induced by chemotherapeutic agents with emphasizing their signaling mechanisms. Graphical Abstract

Emerging evidence has shown that ELA peptide plays a pivotal role in cardiac development and modulation of vascular and cardiac function. In the current work, we sought to examine the possible therapeutic potential of ELA peptide to reduce I/R injury following MI and elucidate the possible mechanisms by which ELA peptide may ameliorate injury and improve heart function after MI. 5 µg/kg of ELA peptide was administrated intraperitoneally in rats once per day for 4 days after ischemia of heart for 30 min. Male Wistar rats were sacrificed at 24 h and 2 weeks after reperfusion. The infarct size was determined by TTC staining 2 weeks after reperfusion. ELISA was employed to measure serum level of myocardial injury markers such as LDH, CK-MB and Troponin I and oxidative stress markers such as membrane lipid peroxidation (MDA), GSH and SOD activities in the first 24 h. Cardiac function was evaluated using echocardiography prior to MI and 2 weeks after reperfusion. After administration of ELA peptide in MI rats, infarct size, serum levels of LDH, CK-MB, Troponin I and tissue levels of MDA were significantly reduced; GSH and SOD activities were markedly increased (p < 0.05). Likewise, ELA peptide improved cardiac function 2 weeks after MI (p < 0.05). ELA peptide administration for 4 days after MI could reduce injury by targeting oxidative stress and improvement of cardiac function. These findings establish a fundamental foundation for future peptide research and therapy.

Ischemic heart diseases (IHD) are one of the major causes of death worldwide. Studies have shown that mesenchymal stem cells can secrete and release conditioned medium (CM) which has biological activities and can repair tissue injury. This study aimed to investigate the effects of human amniotic membrane mesenchymal stem cells (hAMCs)-CM on myocardial ischemia/reperfusion (I/R) injury in rats by targeting oxidative stress. Male Wistar rats (40 rats, weighing 200-250 g) were randomly divided into four groups: Sham, myocardial infarction (MI), MI + culture media, and MI + conditioned medium. MI was induced by ligation of the left anterior descending coronary artery for 30 min. After 15 min of reperfusion, intramyocardial injections of hAMCs-CM or culture media (150 μl) were performed. At the end of the experiment, serum levels of cardiac troponin-I (cTn-I), myocardial levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as cardiac histological changes were evaluated. HAMCs-CM significantly decreased cTn-I and MDA levels and increased SOD and GPx activities ( <0.05). In addition, hAMCs-CM improved cardiac histological changes and decreased myocardial injury percentage ( <0.05). This study showed that hAMCs-CM has cardioprotective effects in the I/R injury condition. Reduction of oxidative stress by hAMCs-CM plays a significant role in this context. Based on the results of this study, it can be concluded that hAMCs-CM can be offered as a therapeutic candidate for I/R injury in the future, but more research is needed.

Background Disparities exist regarding an efficient treatment for stroke. Polyarginines have shown promising neuroprotective properties based on available published studies. Thus, the present study aims to systemically review and analyze existing evidence regarding polyarginine's administration efficacy in animal stroke models. Method Medline, Scopus, Embase, and Web of Science were systematically searched, in addition to manual search. Inclusion criteria were administrating polyarginine peptides in stroke animal models. Exclusion criteria were previous polyarginine administration, lacking a control group, review articles, and case reports. Data were collected and analyzed using STATA 17.0; a pooled standardized mean difference (SMD) with a 95% confidence interval (CI), meta‐regression, and subgroup analyses were presented. Risk of bias, publication bias, and level of evidence were assessed using SYRCLE's tool, Egger's analysis, and Grading of Recommendations Assessment, Development and Evaluation framework, respectively. Results From the 468 searched articles, 11 articles were included. Analyses showed that R18 significantly decreases infarct size (SMD = –0.65; 95% CI: –1.01, –0.29) and brain edema (SMD = –1.90; 95% CI: –3.28, –0.51) and improves neurological outcome (SMD = 0.67; 95% CI: 0.44, 0.91) and functional status (SMD = 0.55; 95% CI: 0.26, 0.85) in stroke animal models. Moreover, R18D significantly decreases infarct size (SMD = –0.75; 95% CI: –1.17, –0.33) and improves neurological outcome (SMD = 0.46; 95% CI: 0.06, 0.86) and functional status (SMD = 0.35; 95% CI: 0.16, 0.54) in stroke models. Conclusion Moderate level of evidence demonstrated that both R18 and R18D administration can significantly improve stroke outcomes in animal stroke models. However, considering the limitations, further pre‐clinical and clinical studies are warranted to substantiate the neuroprotective efficacy of polyarginines for stroke. The findings are summarized in the above figure. Both R18 and R18D showed promising effects on decreasing the infarct size, enhancing functional status, and improving neurological outcome in animal models of stroke. In addition, R18 administration was effective in decreasing brain edema as well.

The clinical use of doxorubicin as a potent chemotherapeutic agent is limited due to its dose-dependent cardiotoxicity. Oxidative stress and inflammatory pathways have a pivotal role in doxorubicin-induced cardiotoxicity. Sumatriptan, a 5-hydroxytryptamine (5-HT)1B/1D agonist that is mainly used to relieve migraine pain, has suggested exerting protective effects in numerous pathological conditions through antiinflammatory properties. The aim of the present study was to investigate the effects of sumatriptan on doxorubicin-induced cardiotoxicity and the contribution of anti-inflammation and antioxidative responses. Cardiotoxicity was induced by the administration of doxorubicin three times a week (2.5 mg/kg i.p) for two consecutive weeks on male rats. The animals were divided into four groups, including Control, Sumatriptan (0.1 mg/kg) received group, doxorubicin received group, and Doxorubicin+Sumatriptan (0.1 mg/kg) received group. Sumatriptan was administered 30 min before every injection of doxorubicin. On the last day of the second week, the body weight, mortality rate, electrocardiogram (ECG) and histopathological changes, cardiac inotropic study, and biochemical factors were evaluated. The loss of body weight, mortality rate, ECG parameters, reduction of papillary muscle contractility force as well as histopathological scores following administration of doxorubicin indicated severe cardiac damage. However, treatment with sumatriptan inhibited the functional and structural impairment induced by doxorubicin. In addition, sumatriptan could significantly reduce cardiac tissue levels of malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α), which were increased in the doxorubicin-treated rats. This study illustrated the protective effects of sumatriptan on decreasing doxorubicin-induced cardiac toxicity and mortality rate in part through inhibition of inflammatory and oxidative stress pathways.

The present study was designed to investigate the effect of early and late administration of phenylephrine during ischemia against regional ischemia-reperfusion injuries in an isolated rat heart model. All animals were randomly divided into experimental groups: (I) IR (Ischemic/ reperfusion): the hearts underwent 35 min of regional ischemia followed by 60 min of reperfusion; (II) 5HD-IR-0: the hearts were perfused for 5 min with 5HD (5-hydroxydecanoate, specific mKATP channel blocker, 100 µM) at the onset of regional ischemia; (III) 5HD-IR-20: the hearts were perfused for 5 min with 5HD 20 min after regional ischemia; (IV) PE-IR-10: the hearts were perfused for 5 min with phenylephrine 10 min after regional ischemia; (V) PE-IR-30: the hearts were perfused for 5 min with phenylephrine (100 µM) 30 min after regional ischemia; (VI) PE-5HD-IR-10 group: the hearts were perfused for 5 min with 5HD at the onset of regional ischemia after which phenylephrine was administrated as in group IV; and (VII) PE-5HD-IR-30: the hearts were perfused for 5 min with 5HD 20 min after the ischemia and then phenylephrine was administrated as in group V. The hemodynamic parameters were recorded throughout the experiment. Ischemia-induced arrhythmias, myocardial infarct size (IS), creatin kinase-MB isoenzyme (CK-MB), plasma lactate dehydrogenase (LDH) activities, and coronary blood flow (CBF) were measured in all animals. Perfusion of phenylephrine 30 min after the regional ischemia curtailed the myocardial infarct size, reduced CK-MB, and improved cardiac function and CBF. Administration of 5HD 30 min after the ischemia abolished cardioprotective effects of phenylephrine in the late phase. These results suggest the involvement of mKATP in the mechanism of phenylephrine-induced late preconditioning.