Metformin and Dapagliflozin Attenuate Doxorubicin-Induced Acute Cardiotoxicity in Wistar Rats: An Electrocardiographic, Biochemical, and Histopathological Approach.

Doxorubicin is a widely used anticancer drug whose efficacy is limited due to its cardiotoxicity. There is no ideal cardioprotection available against doxorubicin-induced cardiotoxicity. This study aimed to investigate the anticipated cardioprotective potential of metformin and dapagliflozin against doxorubicin-induced acute cardiotoxicity in Wistar rats. At the beginning of the experiment, cardiac screening of experimental animals was done by recording an electrocardiogram (ECG) before allocating them into the groups. Thereafter, a total of thirty healthy adult Wistar rats (150-200 g) were randomly divided into five groups (n = 6) and treated for eight days as follows: group I (normal control), group II (doxorubicin control), group III (metformin 250 mg/kg/day), group IV (metformin 180 mg/kg/day), and group V (dapagliflozin 0.9 mg/kg/day). On the 7th day of the treatment phase, doxorubicin 20 mg/kg was administered intraperitoneal to groups II, III, IV, and V. On the 9th day (immediately after 48 h of doxorubicin administration), blood was collected from anesthetized animals for glucose, lipid profile, CK-MB & AST estimation, and ECG was recorded. Later, animals were sacrificed, and the heart was dissected for histopathological examination. We found that compared to normal control rats, CK-MB, AST, and glucose were significantly increased in doxorubicin control rats. There was a significant reversal of doxorubicin-induced hyperglycemia in the rats treated with metformin 250 mg/kg compared to doxorubicin control rats. Both metformin (180 mg/kg and 250 mg/kg) and dapagliflozin (0.9 mg/kg) significantly altered doxorubicin-induced ECG changes and reduced the levels of cardiac injury biomarkers CK-MB and AST compared to doxorubicin control rats. Metformin and dapagliflozin protected the cellular architecture of the myocardium from doxorubicin-induced myocardial injury. Current study revealed that both metformin and dapagliflozin at the FDA-recommended antidiabetic doses mitigated doxorubicin-induced acute cardiotoxicity in Wistar rats. The obtained data have opened the perspective to perform chronic studies and then to clinical studies to precisely consider metformin and dapagliflozin as potential chemoprotection in the combination of chemotherapy with doxorubicin to limit its cardiotoxicity, especially in patients with comorbid conditions like type II diabetes mellitus.

α-tocopherol as a selective modulator of toxicogenic damage induced by antineoplastic agents cyclophosphamide and doxorubicin.

The aim of this study was to determine the oxidative/antioxidative effects, modulatory and selective potential of α-tocopherol (vitamin E) on antineoplastic drug-induced toxicogenetic damage. The toxicity, cytotoxicity and genotoxicity induced by antineoplastic agents cyclophosphamide (CPA) and doxorubicin (DOX) was examined utilizing as models Saccharomyces cerevisiae, Allium cepa, Artemia salina and human peripheral blood mononuclear cells (PBMCs) in the presence of α-tocopherol. For these tests, concentrations of α- tocopherol 100 IU/ml (67mg/ml), CPA 20 µg/ml, DOX 2 µg/ml were used. The selectivity of α-tocopherol was assessed by the MTT test using human mammary gland non-tumor (MCF10A) and tumor (MCF-7) cell lines. Data showed cytoplasmic and mitochondrial oxidative damage induced by CPA or DOX was significantly diminished by α-tocopherol in S. cerevisiae. In addition, the toxic effects on A. salina and cytotoxic and mutagenic effects on A. cepa were significantly reduced by α-tocopherol. In PBMCs, α-tocopherol alone did not markedly affect these cells, and when treated in conjunction with CPA or DOX, α-tocopherol reduced the toxicogenetic effects noted after antineoplastic drug administration as evidenced by decreased chromosomal alterations and lowered cell death rate. In human mammary gland non-tumor and tumor cell lines, α-tocopherol produced selective cytotoxicity with 2-fold higher effect in tumor cells. Evidence indicates that vitamin E (1) produced anti-cytotoxic and anti-mutagenic effects against CPA and DOX (2) increased higher selectivity toward tumor cells, and (3) presented chemoprotective activity in PBMCs.

King Oyster Mushroom, Pleurotus eryngii (Agaricomycetes), Extract Can Attenuate Doxorubicin-Induced Lung Damage by Inhibiting Oxidative Stress in Rats.

Doxorubicin (DOX), a broad spectrum chemotherapeutic, has toxic effects on healthy tissues. Mitochondrial processes and oxidative stress act in the DOX-induced toxicity, therefore antioxidant therapies are widely used. The study was aimed to evaluate the therapeutic potential of Pleurotus eryngii extract (PEE), an extract of a fungus with antioxidant properties, against DOX-induced lung damage. Rats were divided into Control, DOX, DOX + PEE, and PEE groups (n = 6). DOX was administered intraperitoneally in a single dose (10 mg/kg BW) and PE (200 mg/kg BW) was administered by oral gavage every other day for 21 days. Histopathological evaluations, immunohistochemical analyses, total oxidant status (TOS)/total antioxidant status (TAS) method, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis were performed. DOX led to severe histopathological disruptions in rat lungs. Also, DOX remarkably increased the expression of dynamin 1 like (DRP1) and decreased the expression of mitofusin 1 (MFN1) and mitofusin 2 (MFN2) genes, which are related to mitochondrial dynamics. Moreover, DOX caused an increase in TOS/ TAS and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. On the other hand, PEE treatment remarkably normalized the histopathological findings, mitochondrial dynamics-related gene expressions, markers of oxidative stress, and DNA damage. The present study signs out that PEE can ameliorate the DOX-mediated lung toxicity and the antioxidant mechanism associated with mitochondrial dynamics can have a role in this potent therapeutic effect.

Serum and glucocorticoid inducible kinase 1 modulates mitochondrial dysfunction and oxidative stress in doxorubicin-induced cardiomyocytes by regulating Hippo pathway via Neural precursor cell-expressed developmentally down-regulated 4 type 2.

Doxorubicin (Dox) was reported to cause mitochondrial dysfunction and oxidative stress in cardiomyocytes, leading to cardiomyocyte apoptosis and ultimately heart failure. Serum and glucocorticoid inducible kinase 1 (SGK1) participates in the progression of various cardiovascular diseases. Thus, we aimed to explore the role and regulatory mechanism of SGK1 in Dox-induced cardiomyocyte injury. The expression of SGK1 was evaluated in blood samples of heart failure children, and in myocardial tissues and blood samples of Dox-induced rats. Subsequently, we treated cardiomyocytes with Dox in vitro. A gain-of-function assay was performed to assess the effects of SGK1 on mitochondrial dysfunction and oxidative stress in Dox-induced cardiomyocytes. Furthermore, the modulation of SGK1 on Neural precursor cell-expressed developmentally down-regulated 4 type 2 (NEDD4-2) expression and the subsequent Hippo pathway was validated. In our study, we found that SGK1 was downregulated in blood samples of heart failure children, as well as myocardial tissues and blood samples of Dox-induced rats. SGK1 overexpression alleviated the decreases of mitochondrial complex activity, mitochondrial membrane potential, adenosine triphosphate (ATP) content and ATP synthetase activity stimulated by Dox. Besides, SGK1 overexpression reversed the promoting effects of Dox on oxidative stress and apoptosis. Mechanistically, SGK1 overexpression inhibited the expression of NEDD4-2 and blocked the subsequent activation of Hippo pathway. NEDD4-2 overexpression or activation of Hippo reversed the protective effects of SGK1 overexpression on Dox-induced cardiomyocyte injury. In conclusion, our results revealed that SGK1 modulated mitochondrial dysfunction and oxidative stress in Dox-induced cardiomyocytes by regulating Hippo pathway via NEDD4-2.

Protective role of cezanne in doxorubicin-induced cardiotoxicity by inhibiting autophagy, apoptosis and oxidative stress.

Doxorubicin (DOX) is frequently used in clinical practice for its broad-spectrum effects. However, its benefit is limited by a series of complications, including excessive apoptosis and autophagy of cardiomyocytes, overproduction of reactive oxygen species (ROS) and high level of oxidative stress. As a new protein, OTU domain-containing 7B (OTUD7B), also called Cezanne, has been reported to regulate many pathological processes. However, whether it plays a role in DOX-induced cardiotoxicity is still unclear. We discovered that the Cezanne level was significantly increased in DOX-treated neonatal rat cardiomyocytes (NRCMs) and C57BL/6 J mice hearts. In vitro, the knockdown of Cezanne with adenovirus in NRCMs significantly worsened DOX-induced apoptosis, autophagy and oxidative stress, while Cezanne overexpression showed opposite results. In vivo, the overexpression of Cezanne using cardiomyocyte-targeted adeno-associated virus 9 (AAV9) significantly reduced cardiomyocyte apoptosis, autophagy and oxidative stress level when C57BL/6 J mice were subjected to DOX. Mechanistically, the overexpression of Cezanne significantly reversed the in-activation of the PI3K/AKT/mTOR pathway induced by DOX, while the inhibitors of this pathway abolished the effect of Cezanne, suggesting that the PI3K/AKT/mTOR pathway plays a role in the protective function of Cezanne. These findings indicate that Cezanne could ameliorate DOX-induced cardiotoxicity by attenuating the apoptosis and autophagy of cardiomyocytes and decreasing the level of oxidative stress.

Cardioprotective effect of crude polysaccharide fermented by Trametes Sanguinea Lyoyd on doxorubicin-induced myocardial injury mice.

Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its clinical application is greatly limited because of the cardiotoxicity. Thus, exploration of effective therapies against DOX-induced cardiotoxicity is necessary. The aim of this study is to investigate the effects and possible mechanisms of Trametes Sanguinea Lyoyd fermented crude polysaccharide (TSLFACP) against DOX-induced cardiotoxicity. We investigated the protective effects of TSLFACP on myocardial injury and its possible mechanisms using two in vitro cells of DOX-treated cardiomyocytes H9C2 and embryonic myocardial cell line CCC-HEH-2 and a in vivo mouse model of DOX-induced myocardial injury. We found that TSLFACP could reverse DOX-induced toxicity in H9C2 and CCC-HEH-2 cells. Similarly, we found that when pretreatment with TSLFACP (200 mg/kg, i.g.) daily for 6 days, DOX-induced myocardial damage was attenuated, including the decrease in serum myocardial injury index, and the amelioration in cardiac histopathological morphology. Additionally, immunohistochemistry and western blotting were used to identify the underlying and possible signal pathways. We found that TSLFACP attenuated the expression of LC3-II, Beclin-1 and PRAP induced by DOX. In conclusion, our results demonstrated that TSLFACP could protect against DOX-induced cardiotoxicity by inhibiting autophagy and apoptosis.

Targeting Energy Protection as a Novel Strategy to Disclose Di'ao Xinxuekang against the Cardiotoxicity Caused by Doxorubicin.

Doxorubicin (DOX) can induce myocardial energy metabolism disorder and further worsen heart failure. "Energy protection" is proposed as a new cardiac protection strategy. Previous studies have found that Di'ao Xinxuekang (DXXK) can improve doxorubicin-induced cardiotoxicity in mice by inhibiting ferroptosis. However, there are very few studies associating DXXK and energy protection. This study aims to explore the "energy protection" effect of DXXK on cardiotoxicity induced by DOX. A DOX-induced cardiotoxicity model established in rats and H9c2 cells are used to analyze the therapeutic effects of DXXK on serum indexes, cardiac function indexes and cardiac histopathology. The metabonomic methods were used to explore the potential mechanism of DXXK in treating DOX-induced cardiotoxicity. In addition, we also observed the mitochondrial- and autophagy-related indicators of myocardial cells and the mRNA expression level of the core target regulating energy-metabolism-related pathways. Our results indicated that DXXK can improve cardiac function, reduce myocardial enzymes and alleviate the histological damage of heart tissue caused by DOX. In addition, DXXK can improve mitochondrial damage induced by DOX and inhibit excessive autophagy. Metabonomics analysis showed that DOX can significantly affects the pathways related to energy metabolism of myocardial cells, which are involved in the therapeutic mechanism of DXXK. In conclusion, DXXK can treat DOX-induced cardiotoxicity through the AMPK-mediated energy protection pathway.

Untargeted metabolomics reveals the combination effects and mechanisms of Huangqi-fuzi herb-pair against doxorubicin-induced cardiotoxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Qifu decoction (QFD) is a famous traditional Chinese medicine (TCM) composed of Astragali Radix (HuangQi) and Aconiti Lateralis Radix Praeparaia (Fuzi), which can alleviate doxorubicin (DOX)-induced cardiotoxicity (DIC). However, its protective mechanism remains obscured. AIM OF THE STUDY: The present study aimed to uncover the cardioprotective mechanism and the synergistic effect of QFD against DIC in mice. MATERIALS AND METHODS: The cardioprotective activity of QFD against DIC was assessed by electrocardiogram, serum biochemical assays and histopathology. Mass spectrometry-based metabolomic approach was conducted to elucidate the preventive mechanisms of QFD, HuangQi decoction (HQD), and Fuzi decoction (FZD) against DIC. QFD, HQD, FZD-targeted metabolic pathways were identified and compared to investigate the synergistic mechanism of QFD by computational systems analysis. Quantitative real-time PCR (qRT-PCR) was further employed to validate the key metabolic pathways at the level of the gene. RESULTS: The electrocardiogram combined with the biochemical analysis and histopathology showed that the protection effects were sorted as QFD > HQD ≈ FZD. A total of 41 metabolites contributing to DIC were identified in the mice serum, among which 32, 12 and 10 metabolites were significantly reverted by QFD, HQD and FZD, respectively. Metabolic pathway analysis revealed that DOX perturbed 12 metabolic pathways, and QFD, HQD, and FZD-treated groups could significantly reverse 12, 7 and 6 metabolic pathways of these 12 metabolic pathways. Metabolic pathway and qRT-PCR revealed that QFD could protect DIC mainly by regulating energy metabolism, amino acids metabolism, arachidonic acid metabolism and glycerophospholipid metabolism, and HQD and FZD mutually reinforced each other. CONCLUSION: These evidences revealed that QFD was a promising drug candidate for DIC by maintaining metabolic homeostasis. Meanwhile, this work provided a useful approach for evaluating the efficacy and the synergistic effects of TCMs against cardiomyopathy.

Trophoblast Stem-Cell-Derived Exosomes Alleviate Cardiotoxicity of Doxorubicin via Improving Mfn2-Mediated Mitochondrial Fusion.

Doxorubicin (Dox) is an anticancer drug widely used in tumor chemotherapy, but it has the side-effect of cardiotoxicity, which is closely related to mitochondrial damage. Mitochondrial dynamics is a quality control mechanism that usually helps to maintain a healthy mitochondrial pool. Trophoblast stem cell-derived exosomes (TSC-Exos) have been shown to protect cardiomyocytes from DOX-induced cardiotoxicity. To explore whether the cardioprotective role is mediated by the regulation of mitochondrial dynamic mechanism, TSC-Exos were isolated from human trophoblast stem cells by ultracentrifugation and characterized by Western blot and transmission electron microscopy. Cellular experiments of H9c2 cardiomyocytes co-cultured with Dox and TSC-Exos were performed in vitro to determine the levels of reactive oxygen species generation and apoptosis level. An animal model of heart failure was established by intraperitoneal injection of Dox in vivo, therapy mice were received additional intracardiac injection of TSC-Exos, then, the cardiac function, cardiomyocyte apoptosis and mitochondrial fragmentation were ameliorated. Histology assays suggest that Dox caused an increased tendency of mitochondrial fission, which was manifested by a decrease in the average size of mitochondria. By receiving TSC-Exos treatment, this effect was eliminated. In summary, these results suggest that TSC-Exos alleviate DOX-induced cardiotoxicity through antiapoptotic effect and improving mitochondrial fusion with an increase in Mfn2 expression. This study is the first to provide a potential new treatment scheme for the treatment of heart failure from the perspective of the relationship between TSC-Exos and mitochondrial dynamics.

The Protective Effect of Lasia spinosa (Linn.) Dissipates Chemical-Induced Cardiotoxicity in an Animal Model.

Lasia spinosa (L.) Thwaites is a medicinal plant of enormous traditional use with insufficient scientific evidence. This research screened the antioxidative effect of L. spinosa extracts by measuring the total phenolic content, total flavonoid content, DPPH free radical scavenging activity, ABTS scavenging activity, Iron-chelating activity, and Ferric reducing power followed by an evaluation of in vivo cardioprotective effect in doxorubicin-induced Wistar Albino rats. Phytochemical characterization was made by Gas Chromatography-Mass Spectroscopic analysis. L. spinosa showed an excellent antioxidative effect while methanol leaf extract (LSM) was found to be more potent than ethyl acetate leaf extract (LSE) in scavenging the free radicals. Intraperitoneal injection of doxorubicin caused a significant (P < 0.001) increase in lactate dehydrogenase (LDH), creatine kinase (CK-MB), C-reactive protein (CRP), and Cardiac troponin I. Pretreatment with orally administrated (LSM100 and LSM200 mg/kg b.w.) daily for 10 days showed a decrease in the cardiac markers, lipid profiles, especially triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and an increase of high-density lipoprotein (HDL) compared to the disease control group. LSM200 was found to significantly (P < 0.05) decrease the levels of CK-MB and LDH. It also restored TC, TG, and LDL levels compared to the doxorubicin-induced cardiac control group. The protective role of LSM was further confirmed by histopathological examination. This study thus demonstrates that L. spinosa methanol extract could be approached as an alternative supplement for cardiotoxicity, especially in the chemical-induced toxicity of cardiac tissues.

Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice.

AIMS: Oxidative stress and inflammation have been linked to doxorubicin (DOX)-induced cardiotoxicity, while the exact molecular processes are currently under investigation. The goal of this study is to investigate Metformin's preventive role in cardiotoxicity induced by DOX. MATERIALS AND METHODS: Male albino mice were divided randomly into 4 groups. Metformin (Met) 200 mg/kg orally (p.o.) was given either alone or when combined with a single DOX (15 mg/kg; i.p.). A control group of 5 mice was also provided. Met was initiated 7 days before DOX, lasting for 14 days. Besides, docking studies of Met towards HMGB1, NF-kB, and caspase 3 were performed. KEY FINDINGS: Heart weight, cardiac troponin T (cTnT), creatine kinase Myocardial Band (CK-MB) levels, malondialdehyde (MDA), and nitric oxide (NO) contents all increased significantly when comparing the DOX group to the control normal group. Conversely, there was a substantial decline in superoxide dismutase (SOD) and glutathione peroxidase (GSH). DOX group depicts a high expression of TLR4, HMGB1, and caspase 3. Immunohistochemical staining revealed an increase in NLRP3 inflammasome and NF-κB expressions alongside histopathological modifications. Additionally, Met dramatically decreased cardiac weight, CK-MB, and cTnT while maintaining the tissues' histological integrity. Inflammatory biomarkers, including HMGB1, TLR4, NF-κB, inflammasome, and caspase 3 were reduced after Met therapy. Furthermore, molecular docking studies suggested the antagonistic activity of Met towards HMGB1, NF-κB, and caspase 3 target receptors. SIGNIFICANCE: According to recent evidence, Met is a desirable strategy for improving cardiac toxicity produced by DOX by inhibiting the HMGB1/NF-κB inflammatory pathway, thus preserving heart function.

Nifuroxazide mitigates doxorubicin-induced cardiovascular injury: Insight into oxidative/NLRP3/GSDMD-mediated pyroptotic signaling modulation.

Doxorubicin (DOX) is a widely used powerful anthracycline for treatment of many varieties of malignancies; however its cumulative and dose-dependent cardio-toxicity has been limited its clinical use. In the current study, in vivo and in vitro (neonatal rat's cardiomyocytes) experiments were conducted to identify the impact of nifuroxazide (NIFU) on DOX-induced cardiomyopathy, vascular injury, and hemato-toxcity and plot the underlying regulatory mechanisms. Cardiovascular injury was induced in vivo by I.P. injection of an overall dose of DOX (21 mg/kg) administered (3.5 mg/kg) twice weekly for 21 days. NIFU (10 and 30 mg/kg) was administered orally once daily for 21 days, 1 week after DOX injection initiation. In vivo experiments confirmed NIFU to restore blood cells counts and hemoglobin concentration. Moreover, NIFU normalized the myocardial functional status as confirmed by ECG examination and myocardial injury markers; CK-MB, LDH, and AST. NIFU restored the balance between TAC and both of ROS and MDA and down-regulated the protein expression of TLR4, NF-kB, TXNIP, NLR-family pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, and GSDMD-N terminal, with inhibition of the up-stream of NLRP3 and the down-stream DOX-induced pyroptosis. The in vitro assay confirmed well preserved cardiomyocytes' architecture, amelioration of NLRP3/IL-1 ß-mediated cell pyroptosis, enhanced cell viability, and improved spontaneous beating. Moreover, NIFU normalized the disturbed aortic oxidant-antioxidant balance; enhanced eNOS- mediated endothelial relaxation, and down regulated IL-1ß expression. Thus, NIFU may be proposed to serve as a cardioprotective agent to attenuate DOX-induced cardio-toxicity and vascular injury.

Protective effect of gallic acid on doxorubicin-induced ovarian toxicity in mouse.

The aims of the present study were to evaluate the protective effects of gallic acid against doxorubicin-induced ovarian toxicity in mice, and to verify the possible involvement of PI3K and mTOR signaling pathway members (PTEN, Akt, FOXO3a and rpS6) in the gallic acid protective actions. Mice were pretreated with NaCl (0.15 M, p.o.) (control and doxorubicin groups) or gallic acid (50, 100 or 200 mg/kg body weight, p.o.) once daily, for 5 days, and on the third day of treatment, after 1 h of treatment administration, the mice received saline solution (i.p.) (control group) or doxorubicin (10 mg/kg of body weight, i.p.). Next, the ovaries were harvested for histological (follicular morphology and activation), fluorescence (GSH and mitochondrial activity), and immunohistochemical (PCNA, cleaved caspase-3, TNF-α, p-PTEN, Akt, p-Akt, p-rpS6 and p-FOXO3a) analyses. The results showed that cotreatment with 50 mg/kg gallic acid plus doxorubicin preserved the percentage of normal follicles and cell proliferation, reduced the percentage of cleaved caspase-3 follicles, prevented inflammation, and increased GSH concentrations and mitochondrial activity compared to doxorubicin treatment alone. Furthermore, cotreatment 50 mg/kg gallic acid plus doxorrubicin increased expression of Akt, p-Akt, p-rpS6 and p-FOXO3a compared to the doxorubicin alone. In conclusion, 50 mg/kg gallic acid protects the mouse ovary against doxorubicin-induced damage by improving GSH concentrations and mitochondrial activity and cellular proliferation, inhibiting inflammation and apoptosis, and regulating PI3K and mTOR signaling pathway.

Cardioprotective effects of minocycline against doxorubicin-induced cardiotoxicity.

BACKGROUND: Doxorubicin (Dox)-induced cardiotoxicity has limited its use. Inflammation, oxidative stress, and apoptosis have important roles in Dox-induced cardiotoxicity. Minocycline (Min) is an antibiotic with anti-inflammatory, anti-oxidant and anti-apoptotic properties. Here, the cardioprotective effects of Min against Dox-induced cardiotoxicity in adult male rats were evaluated. METHODS: Forty-two adult male rats were divided into six groups including control group (normal saline), Dox group, Min groups (Min 45 mg/kg and Min 90 mg/kg), and treatment groups (Dox + Min 45 mg/kg and Dox + Min 90 mg/kg). Dox (2.5 mg/kg) was administered three times a week for two weeks, and Min once a day for three weeks via intraperitoneal route. Cardiac tissue sections were stained with hematoxylin and eosin for histological examination. The activities of lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) in serum as well as the activity of catalase and superoxide dismutase (SOD) in cardiac tissue were measured. Cardiac tissue levels of malondialdehyde (MDA), TNF-α, and IL-1ß were also measured using ELISA. RESULTS: Compared with the Dox group, treatment with Min significantly decreased the activity of LDH and CK-MB. Min also increased the activity of catalase and SOD in the tissue samples. The results showed that the levels of MDA, TNF-α, and IL-1ß in cardiac tissue samples were significantly lower in the Min groups compared with the Dox group. In addition, histopathological results showed that Min reduced the tissue damage caused by Dox. CONCLUSION: Min reduced Dox-induced cardiotoxicity. The anti-oxidant and anti-inflammatory properties of Min may contribute to its protective effects.

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis.

Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 µg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1ß, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM's antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity.

Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways.

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.

Magnesium hexacyanoferrate nanocatalysts attenuate chemodrug-induced cardiotoxicity through an anti-apoptosis mechanism driven by modulation of ferrous iron.

Distressing and lethal cardiotoxicity is one of the major severe side effects of using anthracycline drugs such as doxorubicin for cancer chemotherapy. The currently available strategy to counteract these side effects relies on the administration of cardioprotective agents such as Dexrazoxane, which unfortunately has unsatisfactory efficacy and produces secondary myelosuppression. In the present work, aiming to target the characteristic ferrous iron overload in the doxorubicin-contaminated cardiac microenvironment, a biocompatible nanomedicine prepared by the polyvinylpyrrolidone-directed assembly of magnesium hexacyanoferrate nanocatalysts is designed and constructed for highly efficient intracellular ferrous ion capture and antioxidation. The synthesized magnesium hexacyanoferrate nanocatalysts display prominent superoxide radical dismutation and catalytic H2O2 decomposition activities to eliminate cytotoxic radical species. Excellent in vitro and in vivo cardioprotection from these magnesium hexacyanoferrate nanocatalysts are demonstrated, and the underlying intracellular ferrous ion traffic regulation mechanism has been explored in detail. The marked cardioprotective effect and biocompatibility render these magnesium hexacyanoferrate nanocatalysts to be highly promising and clinically transformable cardioprotective agents that can be employed during cancer treatment.

Paricalcitol Improves the Angiopoietin/Tie-2 and VEGF/VEGFR2 Signaling Pathways in Adriamycin-Induced Nephropathy.

Renal endothelial cell (EC) injury and microvascular dysfunction contribute to chronic kidney disease (CKD). In recent years, increasing evidence has suggested that EC undergoes an endothelial-to-mesenchymal transition (EndoMT), which might promote fibrosis. Adriamycin (ADR) induces glomerular endothelial dysfunction, which leads to progressive proteinuria in rodents. The activation of the vitamin D receptor (VDR) plays a crucial role in endothelial function modulation, cell differentiation, and suppression of the expression of fibrotic markers by regulating the production of nitric oxide (NO) by activating the endothelial NO synthase (eNOS) in the kidneys. This study aimed to evaluate the effect of paricalcitol treatment on renal endothelial toxicity in a model of CKD induced by ADR in rats and explore mechanisms involved in EC maintenance by eNOS/NO, angiopoietins (Angs)/endothelium cell-specific receptor tyrosine kinase (Tie-2, also known as TEK) and vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) axis. The results show that paricalcitol attenuated the renal damage ADR-induced with antiproteinuric effects, glomerular and tubular structure, and function protection. Furthermore, activation of the VDR promoted the maintenance of the function and structure of glomerular, cortical, and external medullary endothelial cells by regulating NO production. In addition, it suppressed the expression of the mesenchymal markers in renal tissue through attenuation of (transforming growth factor-beta) TGF-ß1/Smad2/3-dependent and downregulated of Ang-2/Tie-2 axis. It regulated the VEGF/VEGFR2 pathway, which was ADR-deregulated. These effects were associated with lower AT1 expression and VDR recovery to renal tissue after paricalcitol treatment. Our results showed a protective role of paricalcitol in the renal microvasculature that could be used as a target for treating the beginning of CKD.

Regular Supplementation with Antioxidants Rescues Doxorubicin-Induced Bone Deformities and Mineralization Delay in Zebrafish.

Osteoporosis is characterized by an abnormal bone structure with low bone mass and degradation of microarchitecture. Oxidative stress induces imbalances in osteoblast and osteoclast activity, leading to bone degradation, a primary cause of secondary osteoporosis. Doxorubicin (DOX) is a widely used chemotherapy drug for treating cancer, known to induce secondary osteoporosis. The mechanism underlying DOX-induced bone loss is still not fully understood, but one of the relevant mechanisms is through a massive accumulation of reactive oxygen and nitrogen species (i.e., ROS and NOS) leading to oxidative stress. We investigated the effects of antioxidants Resveratrol and MitoTEMPO on DOX-induced bone impairment using the zebrafish model. DOX was shown to increase mortality, promote skeletal deformities, induce alterations on intestinal villi, impair growth and mineralization and significantly downregulate osteoblast differentiation markers osteocalcin 2 and osterix/sp7. Lipid peroxidation was significantly increased in DOX-supplemented groups as compared to control and antioxidants, suggesting ROS formation as one of the key factors for DOX-induced bone loss. Furthermore, DOX affected mineral contents, suggesting an altered mineral metabolism. However, upon supplementation with antioxidants, DOX-induced effects on mineral content were rescued. Our data show that supplementation with antioxidants effectively improves the overall growth and mineralization in zebrafish and counteracts DOX-induced bone anomalies.

LCZ696 protects against doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via AKT/SIRT3/SOD2 signaling pathway activation.

Doxorubicin (DOX) is an effective and widely used anticancer drug but has limited clinical applicability because of its cardiotoxicity. Ferroptosis plays a key role in DOX-induced cardiac damage and cardiomyocyte cell death. The inhibition of ferroptosis reverses DOX-induced cardiotoxicity (DIC). LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, protects against DIC. However, the mechanism of action of LCZ696, especially its effect on ferroptosis, is incompletely understood. This study investigates the cardioprotective effects of LCZ696 on DIC in vivo and in vitro.Cardiotoxicity was induced in Wistar rats by tail intravenous injection of 2.5 mg/kg DOX once a week for six weeks. Rats and H9c2 cells were treated with or without LCZ696 to determine the cardioprotective role and underlying mechanisms of LCZ696 against DIC. To assess the role of SIRT3 and correlated pathways in ferroptosis, SIRT3 knockout was performed using lentiviral vectors, and AKT was inhibited with LY294002. LCZ696 significantly attenuated DIC by decreasing the concentrations of lipid reactive oxygen species and malondialdehyde and increasing the levels of glutathione peroxidase-4 and reduced glutathione in cells and heart tissues. Moreover, LCZ696 remodeled myocardial structures and improved heart ventricular function in DOX-treated rats. LCZ696 treatment increased SIRT3 expression and deacetylated its target gene SOD2, and these changes were mediated by AKT activation. SIRT3 knockdown and AKT inhibition induced lipid peroxidation and reduced the protective effect of LCZ696 in H9c2 cells. Collectively,LCZ696 prevents DIC by inhibiting ferroptosis via AKT/SIRT3/SOD2 signaling pathway activation. Thus, LZC696 is a potential therapeutic strategy for DIC.