The Role of mTOR in the Doxorubicin-Induced Cardiotoxicity: A Systematic Review.

Doxorubicin (DOX) is a chemotherapy drug known to induce metabolic changes in the heart, leading to potential heart toxicity. These changes impact various cellular functions and pathways such as disrupting the mechanistic target of rapamycin (mTOR) signaling pathway. The study aimed to investigate the effect of DOX on the mTOR pathway through an in vivo systematic review. Databases were searched on September 11, 2023. We finally included 30 in vivo studies that examined the mTOR expression in cardiac tissue samples. The present study has shown that the PI3K/AKT/mTOR, the AMPK/mTOR, the p53/mTOR signaling, the mTOR/TFEB pathway, the p38 MAPK/mTOR, the sestrins/mTOR, and the KLF15/eNOS/mTORC1 signaling pathways play a crucial role in the development of DOX-induced cardiotoxicity. Inhibition or dysregulation of these pathways can lead to increased oxidative stress, apoptosis, and other adverse effects on the heart. Strategies that target and modulate the mTOR pathways, such as the use of mTOR inhibitors like rapamycin, have the potential to enhance the anticancer effects of DOX while also mitigating its cardiotoxic side effects.

Molecular mechanisms involved in therapeutic effects of natural compounds against cisplatin-induced cardiotoxicity: a review.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various cancers. However, the clinical use of cisplatin is limited by its cardiotoxic side effects. The primary mechanisms implicated in this cardiotoxicity include mitochondrial dysfunction, oxidative stress, inflammation, and apoptotic. Numerous natural compounds (NCs) have been introduced as promising protective factors against cisplatin-mediated cardiac damage. The current review summarized the potential of various NCs as cardioprotective agents at the molecular levels. These compounds exhibited potent antioxidant and anti-inflammatory effects by interaction with the PI3K/AKT, AMPK, Nrf2, NF-κB, and NLRP3/caspase-1/GSDMD pathways. Generally, the modulation of these signaling pathways by NCs represents a promising strategy for improving the therapeutic index of cisplatin by reducing its cardiac side effects.

Cardioprotective effects of losartan and diminazene against the ischemia/reperfusion injury in hyperthyroidism rats.

Hyperthyroidism is a condition where the thyroid gland produces high levels of thyroid hormone. Heart diseases are one of the main complications of hyperthyroidism. Several studies have shown that losartan (LOS) and diminazene aceturate (DIZE) possess cardioprotection effects against cardiac hypertrophy, ischemic heart disease, and heart failure. The research aimed to investigate the cardioprotection of LOS, DIZE, and their combination in the case of levothyroxine (LT4)-induced cardiomyopathy in rats. Hyperthyroidism was induced by LT4 in drinking water (12 mg/L) for 28 days. LOS (10 mg/kg, orally) and/or DIZE (15 mg/kg, subcutaneously) were administrated in rats with hyperthyroidism for 28 days. Decreased serum creatine kinase myoglobin and lactate dehydrogenase levels and cardiac hypertrophy by DIZE and combination therapy in hyperthyroidism rats have been reported. Cardiac hemodynamic findings showed that DIZE and its combination with LOS decreased the LT4-mediated left ventricular developed pressure (LVDP), rate pressure product (RPP), and RPP recovery percentage. Elevated cardiac oxidative stress and inflammation were confirmed by decreasing cardiac superoxide dismutase (SOD) activity and increasing the total oxidative stress and tumor necrosis factor-alpha (TNF-α) levels. SOD activity and TNF-α level were reversed by LOS and DIZE administration, respectively. Generally, DIZE and combination therapy with LOS improved cardiac dysfunction caused by hyperthyroidism in rats, whereas LOS alone has not been able to effectively respond to this dysfunction.

Cardioprotective effect of naringin against the ischemia/reperfusion injury of aged rats.

Aging is known as a main risk factor in the development of cardiovascular diseases. Naringin (NRG) is a flavonoid compound derived from citrus fruits. It possesses a wide spectrum of pharmacological properties, including antioxidant anti-inflammatory, and cardioprotective. This investigation aimed to assess the cardioprotective effect of NRG against the ischemia/reperfusion (I/R) injury in aged rats. In this study, D-galactose (D-GAL) at the dose of 150 mg/kg/day for 8 weeks was used to induce aging in rats. Rats were orally gavaged with NRG (40 or 100 mg/kg/day), in co-treatment with D-GAL, for 8 weeks. The Langendorff isolated heart was used to evaluate the effect of NRG on I/R injury in aged rats. NRG treatment diminished myocardial hypertrophy and maximum contracture level in aged animals. During the pre-ischemic phase, reduced heart rate was normalized by NRG. The effects of D-GAL on the left ventricular end diastolic pressure (LVDP), the rate pressure product (RPP), and the minimum and maximum rate of left ventricular pressure (±dp/dt) improved by NRG treatment in the perfusion period. NRG also enhanced post-ischemic recovery of cardiac functional parameters (± dp/dt, and RPP) in isolated hearts. An increase in serum levels of the lactate dehydrogenase (LDH), the creatine kinase-MB (CK-MB), and the tumor necrosis factor-alpha (TNF-α) were reversed by NRG in aged rats. It also normalized the D-GAL-decreased the superoxide dismutase (SOD) activity in the heart tissue. NRG treatment alleviated cardiac injury in aged hearts under conditions of I/R. NRG may improve aging-induced cardiac dysfunction through anti-oxidative and anti-inflammatory mechanisms.

The Role of mTOR in Doxorubicin-Altered Cardiac Metabolism: A Promising Therapeutic Target of Natural Compounds.

Doxorubicin (DOX) is commonly used for the treatment of various types of cancer, however can cause serious side effects, including cardiotoxicity. The mechanisms involved in DOX-induced cardiac damage are complex and not yet fully understood. One mechanism is the disruption of cardiac metabolism, which can impair cardiac function. The mammalian target of rapamycin (mTOR) is a key regulator of cardiac energy metabolism, and dysregulation of mTOR signaling has been implicated in DOX-induced cardiac dysfunction. Natural compounds (NCs) have been shown to improve cardiac function in vivo and in vitro models of DOX-induced cardiotoxicity. This review article explores the protective effects of NCs against DOX-induced cardiac injury, with a focus on their regulation of mTOR signaling pathways. Generally, the modulation of mTOR signaling by NCs represents a promising strategy for decreasing the cardiotoxic effects of DOX.

An overview of immune checkpoint therapy in autoimmune diseases.

Immune checkpoint receptors are critical regulators of initiation and termination of effective immune responses as well as maintain self-tolerance. Since the successful use of immune checkpoint inhibitors in cancer immunotherapy, they gained huge interest to be used in autoimmune diseases treatment. Indeed, abatacept (CTLA4-Ig), as immune checkpoint inhibitors has made major advancement in the treatment of rheumatoid arthritis patients who have failed to respond to csDMARDs or TNF-α inhibitor. Over the past decade, an increasing number of new immune checkpoints have been detected and lots of investigations are in progress to address their potential as possible targets of effective novel immunotherapy. Here we focus on the biological functions and structures of these immune checkpoints, their pharmacological mechanisms, pathogenesis, therapeutic effects, and their related adverse events. We also discuss the application of agonistic or antagonistic agents targeting co-inhibitory or co-stimulatory checkpoints for the treatment of autoimmune diseases. Furthermore, we summarize previous and recent clinical trials utilizing these immune checkpoints in autoimmune diseases. Obviously, the characterization of such processes might help to develop more effective therapeutic agents in the future.

Gallic acid protects against isoproterenol-induced cardiotoxicity in rats.

BACKGROUND: Gallic acid (GA) is a polyphenolic agent with interesting pharmacological impacts on the cardiovascular system. OBJECTIVE: The present study purposed to study the protective effects of GA at 25 and 50 mg/kg against isoproterenol (ISO)-induced cardiac damage in ischemia/reperfusion (I/R) in rats. METHODS: Male Wistar rats were randomly assigned into six groups: Control, Control treated with GA at 25 mg/kg (GA25), Control treated with GA at 50 mg/kg (GA50), Hypertrophic rats induced by ISO (ISO), Hypertrophic rats treated with GA at 25 mg/kg (ISO+GA25), and Hypertrophic rats treated with GA at 50 mg/kg (ISO+GA50). Heart isolation was performed to induce a cardiac I/R injury model. Cardiac hemodynamic parameters were recorded. Serum Lactate Dehydrogenase (LDH) and Creatine Kinase-MB (CK-MB) and cardiac Superoxide dismutases (SOD) levels were evaluated. The gene expression of Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) was assessed. RESULTS: We found that GA at 50 mg/kg was significantly increased cardiac function at post I/R period in ISO-induced hypertrophic hearts. Moreover, it suppressed cardiac hypertrophy, the serum LDH and CK-MB levels in ISO injected rats. Administration of GA at 50 mg/kg was significantly increased SOD level and SERCA2a gene expression in the hypertrophic hearts. CONCLUSION: GA at 50 mg/kg could improve cardiac performance possibly by increasing antioxidant defense enzymes, reducing cell damage, and enhancing SERCA2a gene expression in hypertrophic heart induced by ISO in I/R injury conditions.

Current Advances in the Use of Nanophytomedicine Therapies for Human Cardiovascular Diseases.

Considering the high prevalence of cardiovascular diseases (CVDs), the primary cause of death during the last several decades, it is necessary to develop proper strategies for the prevention and treatment of CVDs. Given the excessive side effects of current therapies, alternative therapeutic approaches like medicinal plants and natural products are preferred. Lower toxicity, chemical diversity, cost-effectiveness, and proven therapeutic potentials make natural products superior compared to other products. Nanoformulation methods improve the solubility, bioavailability, circulation time, surface area-to-volume ratio, systemic adverse side effects, and drug delivery efficiency of these medications. This study intended to review the functionality of the most recent nanoformulated medicinal plants and/or natural products against various cardiovascular conditions such as hypertension, atherosclerosis, thrombosis, and myocardial infarction. Literature review revealed that curcumin, quercetin, and resveratrol were the most applied natural products, respectively. Combination therapy, conjugation, or fabrication of nanoparticles and nanocarriers improved the applications and therapeutic efficacy of herbal- or natural-based nanoformulations. In the context of CVDs prevention and/or treatment, available data suggest that natural-based nanoformulations are considerably efficient, alone or in blend with other herbal/synthetic medicines. However, clinical trials are mandatory to elucidate the safety, cardioprotective effect, and mechanism of actions of nanophytomedicines.

Nanoformulations of natural products for management of metabolic syndrome.

Metabolic syndrome is a common metabolic disorder which has become a public health challenge worldwide. There has been growing interest in medications including natural products as complementary or alternative choices for common chemical therapeutics regarding their limited side effects and ease of access. Nanosizing these compounds may help to increase their solubility, bioavailability, and promisingly enhance their efficacy. This study, for the first time, provides a comprehensive overview of the application of natural-products-based nanoformulations in the management of metabolic syndrome. Different phytochemicals including curcumin, berberine, Capsicum oleoresin, naringenin, emodin, gymnemic acid, resveratrol, quercetin, scutellarin, stevioside, silybin, baicalin, and others have been nanosized hitherto, and their nanosizing method and effect in treatment and alleviating metabolic syndrome have been reviewed and discussed in this study. It has been discovered that there are several pathways or molecular targets relevant to metabolic disorders which are affected by these compounds. Various natural-based nanoformulations have shown promising effect in treatment of metabolic syndrome, and therefore can be considered as future candidates instead of or in conjunction with pharmaceutical drugs if they pass clinical trials successfully.

Protective effect of paracetamol in doxorubicin-induced cardiotoxicity in ischemia/reperfused isolated rat heart.

OBJECTIVE: Doxorubicin (DOX) induces cardiac dysfunction. Paracetamol (APAP) has also been established as an effective cardioprotective agent during ischemia/reperfusion. Therefore, this study aims to evaluate the effect of APAP on DOX-induced cardiotoxicity in ischemia/reperfused isolated rat heart. METHODS: A total of 36 rats were equally divided into four groups: control, DOX (30 min, 20 µM DOX perfusion), APAP (15 min before and after ischemia, 0.35 mM APAP perfusion), and DOX+APAP (perfused with the same protocol in DOX and APAP groups). The isolated hearts were perfused according to the Langendorff method. Cardiac parameters, including left ventricular developed pressure (LVDP), heart rate (HR), coronary flow (CF), and rate pressure product (RPP; LVDP×HR) were measured. Lactate dehydrogenase (LDH) concentration was also assessed. RESULTS: At the end of the baseline period, the RPP, HR, and CF values were lower in the DOX group than in the control group (p<0.01). Meanwhile, there were no significant differences between the values of cardiac function parameters in the DOX+APAP and control groups. In the reperfusion period, the RPP and CF values were significantly increased in the DOX+APAP group compared with the DOX group (p<0.05). Furthermore, the LDH concentration was decreased in the DOX+APAP group compared with the DOX group. CONCLUSION: APAP perfusion protected the hearts against DOX-induced cardiotoxicity in the baseline and ischemia/reperfusion conditions. These findings can be explained by the effect of APAP on antioxidant capacity and mitochondrial permeability transition pores.

Ethyl acetate fraction of Allium hirtifolium improves functional parameters of isolated hearts of diabetic rats.

OBJECTIVE: Allium hirtifolium (Persian shallot) has a hypoglycemic effect on diabetic animals. The aim of this study was to assess the effect of the ethyl acetate fraction of Allium hirtifolium on the function of isolated hearts of diabetic rats. METHODS: The control and diabetic animals were randomly divided into four groups: saline- or extract-treated controls (n=10 and n=6, respectively) and saline- or extract-treated diabetic rats (n=8 and n=9, respectively), which received normal saline or extract for four weeks by daily gavage. The hearts were perfused according to the Langendorff method. Cardiac function parameters, including left ventricular developed pressure (LVDP), heart rate (HR), rate pressure product (RPP; LVDP×HR), and dp/dt were measured. RESULTS: The findings of this study showed that in the extract-treated diabetic rats, LVDP (94.5±9.1 mm Hg, mean±SEM), HR (249±15 beats/min), RPP (22732±1246) and +dp/dt (2598±230) at the baseline were significantly higher than those in the saline-treated diabetic animals, (71.5±4.0), (189±6), (13923±984), and (1701±124), respectively. Furthermore, RPP and HR were also significantly higher than the corresponding values obtained in the saline-treated diabetic rats after ischemia. CONCLUSION: Besides blood glucose lowering action, oral administration of the ethyl acetate fraction of Allium hirtifolium significantly improved the baseline and post-ischemic cardiac function parameters in streptozotocin-induced diabetic rats.

The effects of acetazolamide on ischemia reperfused isolated hearts of 2- and 8-week-old rabbits.

OBJECTIVE: To investigate the effects of acetazolamide on the ischemia-reperfused isolated hearts of 2- and 8-week-old rabbits. METHODS: This study was conducted at the Kermanshah Medical Biology Research Center, Kermanshah, Iran from March to September 2011. Two- (n=17) and 8-week old (n=17) rabbits were separately divided into 2 control (n=9), and test (n=8) groups. Isolated hearts were subjected to 35 minutes ischemia and 30 minutes reperfusion. Acetazolamide (100 microgr/l) was added to the perfusion solution for 10 minutes before ischemia in the test group. Cardiac parameters including ventricular pressure, heart rate (HR), and rate pressure product (RPP) were measured. Data sets were analyzed by t-test. RESULTS: Following acetazolamide administration the change percentage of HR was significantly different in the 2-week (91 +/- 1.1%) compared with the 8-week (96 +/- 0.8%) test groups (p=0.0016). Recovery percentage of RPP in reperfusion was lower (p=0.005) in the 8- (28.9 +/- 3.4%) than the 2-week test groups (45.2 +/- 3.5%). CONCLUSION: The 2-week hearts elicited more rapid response to carbonic anhydrase (CA) inhibition than the 8-week group. However, acetazolamide does not exacerbate ischemia-reperfusion (I/R) injury in the 2-week hearts. Therefore, it was revealed that after inhibition of CA, the age dependent pattern of I/R injury was similar to that of the normal hearts. Inspite of the CA important role in the normal heart function, it is not a determining factor in I/R injury in different ages.