Ginsenoside Rb1 attenuates doxorubicin induced cardiotoxicity by suppressing autophagy and ferroptosis.

Ginsenoside Rb1 (Rb1), an active component isolated from traditional Chinese medicine Ginseng, is beneficial to many cardiovascular diseases. However, whether it can protect against doxorubicin induced cardiotoxicity (DIC) is not clear yet. In this study, we aimed to investigate the role of Rb1 in DIC. Mice were injected with a single dose of doxorubicin (20 mg/kg) to induce acute cardiotoxicity. Rb1 was given daily gavage to mice for 7 days. Changes in cardiac function, myocardium histopathology, oxidative stress, cardiomyocyte mitochondrion morphology were studied to evaluate Rb1's function on DIC. Meanwhile, RNA-seq analysis was performed to explore the potential underline molecular mechanism involved in Rb1's function on DIC. We found that Rb1 treatment can improve survival rate and body weight in Dox treated mice group. Rb1 can attenuate Dox induced cardiac dysfunction and myocardium hypertrophy and interstitial fibrosis. The oxidative stress increase and cardiomyocyte mitochondrion injury were improved by Rb1 treatment. Mechanism study found that Rb1's beneficial role in DIC is through suppressing of autophagy and ferroptosis. This study shown that Ginsenoside Rb1 can protect against DIC by regulating autophagy and ferroptosis.

Doxorubicin as Risk Factor for Fascial Dehiscence After CRS-HIPEC for Peritoneal Metastases.

BACKGROUND/AIM: Among postoperative complications, fascial dehiscence (FD) is registered in up to 10% of patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). This study aimed to evaluate the risk factors related to FD after CRS-HIPEC. PATIENTS AND METHODS: A retrospective analysis of a prospectively maintained database of consecutive patients who underwent CRS-HIPEC between 2015 and 2023 was performed. For each patient, risk factors for postoperative fascial dehiscence were identified using multivariate analysis. RESULTS: During the study period (2018-2023), 217 patients were treated with CRS-HIPEC. The incidence of FD was observed in seven cases (3.2%), which were reoperated with direct fascial closure. In three cases, FD was associated with other grade III-IV complications. Body mass index, (BMI; p=0.024), doxorubicin-based HIPEC (p=0.005), and open technique (p=0.004) were identified as risk factors for FD in univariate analysis. Systemic chemotherapy, prior surgical score, and peritoneal cancer index (PCI) were not associated with an increased risk of FD. In multivariable regression analysis, doxorubicin-based HIPEC and open technique were confirmed as risk factors for FD. CONCLUSION: Although FD is a relatively rare event after CRS-HIPEC, open technique and doxorubicin-based HIPEC were significant predictors of this complication. Specific fascial closure techniques and proper wound care should be considered in high-risk patients.

Astragaloside IV Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting Cardiomyocyte Pyroptosis through the SIRT1/NLRP3 Pathway.

Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug used to treat a wide spectrum of tumors. However, its clinical application is limited due to cardiotoxic side effects. Astragaloside IV (AS IV), one of the major compounds present in aqueous extracts of Astragalus membranaceus, possesses potent cardiovascular protective properties, but the underlying molecular mechanisms are unclear. Thus, the aim of this study was to investigate the effect of AS IV on DOX-induced cardiotoxicity (DIC). Our findings revealed that DOX induced pyroptosis through the caspase-1/gasdermin D (GSDMD) and caspase-3/gasdermin E (GSDME) pathways. AS IV treatment significantly improved the cardiac function and alleviated myocardial injury in DOX-exposed mice by regulating intestinal flora and inhibiting pyroptosis; markedly suppressed the levels of cleaved caspase-1, N-GSDMD, cleaved caspase-3, and N-GSDME; and reversed DOX-induced downregulation of silent information regulator 1 (SIRT1) and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mice. The SIRT1 inhibitor EX527 significantly blocked the protective effects of AS IV. Collectively, our results suggest that AS IV protects against DIC by inhibiting pyroptosis through the SIRT1/NLRP3 pathway.

Severe hyponatremia and diabetes insipidus caused by low-dose cyclophosphamide in breast cancer patients: A case report and literature review.

RATIONALE: Cyclophosphamide (CTX) is widely used in the treatment of malignancies and autoimmune diseases. Although severe hyponatremia caused by low-dose CTX chemotherapy is uncommon, it can lead to serious complications and even death. PATIENT CONCERNS: A 44-year-old woman with left-sided breast cancer suddenly experienced headaches, disorientation and weakness after receiving low-dose neoadjuvant chemotherapy combined with CTX and doxorubicin. DIAGNOSES: The patient pathology showed invasive breast carcinoma. She developed severe hyponatremia and a generalized seizure after completing the first cycle of neoadjuvant chemotherapy with CTX and doxorubicin. Laboratory tests showed a serum sodium of 118 mmol/L (normal range 135-145 mmol/L) and potassium sodium 3.16 mmol/L (normal range 3.5-5.5 mmol/L). Subsequently, the patient developed secondary diabetes insipidus 4 hours after sodium supplementation, her 24-hour urine volume was 4730 mL (normal range 1000-2000 mL/24 hours), and the urine specific gravity decreased to 1.005. INTERVENTIONS: The patient was given intravenous sodium chloride (500 mL of 3%NaCl, 100 mL/hour) and potassium chloride (500 mL of 0.3%KCl, 250 mL/hour). Meanwhile, she was advised to reduce her water intake, and pituitrin was administered to prevent dehydration caused by diabetes insipidus. OUTCOMES: The patient completely recovered after correcting of the serum sodium concentration (137 mmol/L) without any neurological deficits. After discontinuing pituitrin, her 24-hour urine volume was 2060 mL and the urine specific gravity was 1.015. LESSONS: This is a typical case of severe hyponatremia induced by low-dose CTX. Clinicians and healthcare providers should be aware of this potential toxicity, and appropriate monitoring should be implemented.

Beta vulgaris-derived exosome-like nanovesicles alleviate chronic doxorubicin-induced cardiotoxicity by inhibiting ferroptosis.

Dose-dependent heart failure is a major complication of the clinical use of doxorubicin (Dox), one of the most potent chemotherapeutic agents. Effective adjuvant therapy is required to prevent Dox-induced cardiotoxicity. Currently, plant-derived exosome-like nanovesicle (PELNV) has revealed their salubrious antioxidant and immunological regulating actions in various disease models. In this study, we isolated, purified and characterized Beta vulgaris-derived exosome-like nanovesicle (BELNV). Dox or normal saline was given to HL-1 cells (3 µM) and 8-week C57BL/6N mice (5 mg/kg bodyweight per week for 4 weeks) to establish the in vitro and in vivo model of Dox-induced cardiotoxicity. Administration of BELNV significantly alleviated chronic Dox-induced cardiotoxicity in terms of echocardiographic and histological results. A reduced malondialdehyde (MDA), increased ratio of glutathione (GSH) to oxidized glutathione (GSSG) and levels of system xc- and glutathione peroxidase 4 were observed, indicating that DOX-stimulated ferroptosis was reversed by BELNV. Besides, the safety of BELNV was also validated since no liver, spleen, and kidney toxicity induced by BELNV was observed. These findings provide evidence that BELNV may act as a novel therapeutic biomaterial for patients undergoing adverse effects of Dox, at least partly mediated by inhibiting Dox-induced ferroptosis.

Phloretin alleviates doxorubicin-induced cardiotoxicity through regulating Hif3a transcription via targeting transcription factor Fos.

BACKGROUND: Doxorubicin (Dox), a chemotherapeutic agent known for its efficacy, has been associated with the development of severe cardiotoxicity, commonly referred to as doxorubicin-induced cardiotoxicity (DIC). The role and mechanism of action of phloretin (Phl) in cardiovascular diseases are well-established; however, its specific function and underlying mechanism in the context of DIC have yet to be fully elucidated. OBJECTIVE: This research aimed to uncover the protective effect of Phl against DIC in vivo and in vitro, while also providing a comprehensive understanding of the underlying mechanisms involved. METHODS: DIC cell and murine models were established. The action targets and mechanism of Phl against DIC were comprehensively examined by systematic network pharmacology, molecular docking, transcriptomics technologies, transcription factor (TF) prediction, and experimental validation. RESULTS: Phl relieved Dox-induced cell apoptosis in vitro and in vivo. Through network pharmacology analysis, a total of 554 co-targeted genes of Phl and Dox were identified. Enrichment analysis revealed several key pathways including the PI3K-Akt signaling pathway, Apoptosis, and the IL-17 signaling pathway. Protein-protein interaction (PPI) analysis identified 24 core co-targeted genes, such as Fos, Jun, Hif1a, which were predicted to bind well to Phl based on molecular docking. Transcriptomics analysis was performed to identify the top 20 differentially expressed genes (DEGs), and 202 transcription factors (TFs) were predicted for these DEGs. Among these TFs, 10 TFs (Fos, Jun, Hif1a, etc.) are also the co-targeted genes, and 3 TFs (Fos, Jun, Hif1a) are also the core co-targeted genes. Further experiments validated the finding that Phl reduced the elevated levels of Hif3a (one of the top 20 DEGs) and Fos (one of Hif3a's predicted TFs) induced by Dox. Moreover, the interaction between Fos protein and the Hif3a promoter was confirmed through luciferase reporter assays. CONCLUSION: Phl actively targeted and down-regulated the Fos protein to inhibit its binding to the promoter region of Hif3a, thereby providing protection against DIC.

Galangin attenuates doxorubicin-induced cardiotoxicity via activating nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling pathway to suppress oxidative stress and inflammation.

Doxorubicin (DOX) has aroused contradiction between its potent anti-tumor capacity and severe cardiotoxicity. Galangin (Gal) possesses antioxidant, anti-inflammatory, and antiapoptotic activities. We aimed to explore the role and underlying mechanisms of Gal on DOX-induced cardiotoxicity. Mice were intraperitoneally injected with DOX (3 mg/kg, every 2 days for 2 weeks) to generate cardiotoxicity model and Gal (15 mg/kg, 2 weeks) was co-administered via gavage daily. Nuclear factor erythroid 2-related factor 2 (Nrf2) specific inhibitor, ML385, was employed to explore the underlying mechanisms. Compared to DOX-insulted mice, Gal effectively improved cardiac dysfunction and ameliorated myocardial damage. DOX-induced increase of reactive oxygen species, malondialdehyde, and NADPH oxidase activity and downregulation of superoxide dismutase (SOD) activity were blunted by Gal. Gal also markedly blocked increase of IL-1ß, IL-6, and TNF-α in DOX-insulted heart. Mechanistically, Gal reversed DOX-induced downregulation of Nrf2, HO-1, and promoted nuclear translocation of Nrf2. ML385 markedly blunted the cardioprotective effects of Gal, as well as inhibitive effects on oxidative stress and inflammation. Gal ameliorates DOX-induced cardiotoxicity by suppressing oxidative stress and inflammation via activating Nrf2/HO-1 signaling pathway. Gal may serve as a promising cardioprotective agent for DOX-induced cardiotoxicity.

In Vitro Evaluation of Ferutinin Rich-Ferula communis L., ssp. glauca, Root Extract on Doxorubicin-Induced Cardiotoxicity: Antioxidant Properties and Cell Cycle Modulation.

The clinical use of anthracycline Doxorubicin as an antineoplastic drug in cancer therapy is limited by cardiotoxic effects that can lead to congestive heart failure. Recent studies have shown several promising activities of different species of the genus Ferula belonging to the Apiaceae Family. Ferula communis is the main source of Ferutinin-a bioactive compound isolated from many species of Ferula-studied both in vitro and in vivo because of their different effects, such as estrogenic, antioxidant, anti-inflammatory, and also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. However, the potential protective role of Ferutinin in myocardium impairment, caused by chemotherapeutic drugs, still represents an unexplored field. The aim of this study was to test the effects of Ferutinin rich-Ferula communis L. root extract (FcFE) at different concentrations on H9C2 cells. Moreover, we evaluated its antioxidant properties in cardiomyocytes in order to explore new potential therapeutic activities never examined before in other experimental works. FcFE, at a concentration of 0.25 µM, in the H9C2 line, significantly reduced the ROS production induced by H2O2 (50 µM and 250 µM) and traced the cell mortality of the H9C2 co-treated with Ferutinin 0.25 µM and Doxorubicin (0.5 µM and 1 µM) to control levels. These results showed that FcFE could protect against Doxorubicin-induced cardiotoxicity. Further molecular characterization of this natural compound may open the way for testing FcFE at low concentrations in vivo and in clinical studies as an adjuvant in cancer therapy in association with anthracyclines to prevent side effects on heart cells.

Vernonia amygdalina Ethanol Extract Protects against Doxorubicin-Induced Cardiotoxicity via TGFß, Cytochrome c, and Apoptosis.

Doxorubicin (DOX) has been extensively utilized in cancer treatment. However, DOX administration has adverse effects, such as cardiac injury. This study intends to analyze the expression of TGF, cytochrome c, and apoptosis on the cardiac histology of rats induced with doxorubicin, since the prevalence of cardiotoxicity remains an unpreventable problem due to a lack of understanding of the mechanism underlying the cardiotoxicity result. Vernonia amygdalina ethanol extract (VAEE) was produced by soaking dried Vernonia amygdalina leaves in ethanol. Rats were randomly divided into seven groups: K- (only given doxorubicin 15 mg/kgbw), KN (water saline), P100, P200, P400, P4600, and P800 (DOX 15 mg/kgbw + 100, 200, 400, 600, and 800 mg/kgbw extract); at the end of the study, rats were scarified, and blood was taken directly from the heart; the heart was then removed. TGF, cytochrome c, and apoptosis were stained using immunohistochemistry, whereas SOD, MDA, and GR concentration were evaluated using an ELISA kit. In conclusion, ethanol extract might protect the cardiotoxicity produced by doxorubicin by significantly reducing the expression of TGF, cytochrome c, and apoptosis in P600 and P800 compared to untreated control K- (p < 0.001). These findings suggest that Vernonia amygdalina may protect cardiac rats by reducing the apoptosis, TGF, and cytochrome c expression while not producing the doxorubicinol as doxorubicin metabolite. In the future, Vernonia amygdalina could be used as herbal preventive therapy for patient administered doxorubicin to reduce the incidence of cardiotoxicity.

Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506).

PURPOSE: To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4. METHODS: The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3 year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL). We calculated that 252 pts were needed in each treatment group to enable the detection of non-inferiority (non-inferiority margin of 10%). RESULTS: In terms of ITT analysis, 248 pts were finally enrolled. The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm. With a median follow up of 64.1 months, the 3Y DFS was comparable between the two arms (75.8% in FEC3-D3 vs. 75.6% in AC4-D4). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44). CONCLUSION: Six cycles of FEC3-D3 could be an alternative to eight of AC4-D4. Trial registration ClinicalTrials.gov NCT02001506. Registered December 5,2013. https://clinicaltrials.gov/ct2/show/NCT02001506.

Artemether ameliorates adriamycin induced cardiac atrophy in mice.

Adriamycin is a widely used and effective antitumor drug; however, its application is limited by various side effects, including irreversible cardiotoxicity. The central role of cardiac atrophy in Adriamycin­induced cardiotoxicity has been revealed; however, the underlying mechanism of this process remains unclear. Artemether is a well­known Chinese herbal medicine, and its pharmacological action is related to the regulation of mitochondrial function and redox status. The present study determined the effects of artemether on Adriamycin­induced cardiotoxicity and investigated the underlying mechanisms. After mouse model establishment and artemether intervention, experimental methods including pathological staining, immunohistochemistry, immunofluorescence, immunoblotting, ELISA and reverse transcription­quantitative PCR were used to evaluate the therapeutic effect. The results demonstrated that artemether prevented Adriamycin­induced cardiac atrophy and recovered the intercombination of connexin 43 and N­cadherin at the intercalated discs. Artemether also regulated the autophagy pathway and restored the unbalanced ratio of Bax and Bcl­2 in myocardial cells. In addition, the increased serum H2O2 levels after Adriamycin exposure were significantly decreased by artemether, and the mitochondrial alterations and redox imbalance in myocardial cells were also improved to varying degrees. In summary, the findings of the present study provide reliable evidence that artemether could ameliorate cardiac atrophy induced by Adriamycin. This therapeutic approach may be translated to the clinic for preventing drug­induced heart diseases.

AKR1B1 inhibition using NARI-29-an Epalrestat analogue-alleviates Doxorubicin-induced cardiotoxicity via modulating Calcium/CaMKII/MuRF-1 axis.

The clinical use of doxorubicin (Dox) is narrowed due to its carbonyl reduction to doxorubicinol (Doxol) implicating resistance and cardiotoxicity. Hence, in the present study we have evaluated the cardioprotective effect of AKR1B1 (or aldose reductase, AR) inhibitor NARI-29 (epalrestat (EPS) analogue) and its effect in the Dox-modulated calcium/CaMKII/MuRF1 axis. Initially, the breast cancer patient survival associated with AKR1B1 expression was calculated using Kaplan Meier-plotter (KM-plotter). Further, breast cancer, cardiomyoblast (H9c2), and macrophage (RAW 264.7) cell lines were used to establish the in vitro combination effect of NARI-29 and Dox. To develop the cardiotoxicity model, mice were given Dox 2.5 mg/kg (i.p.), biweekly. The effect of AKR1B1 inhibition using NARI-29 on molecular and cardiac functional changes was measured using echocardiography, fluorescence-imaging, ELISA, immunoblotting, flowcytometry, High-Performance Liquid Chromatography with Fluorescence Detection (HPLC-FD) and cytokine-bead array methods. The bioinformatics data suggested that a high expression of AKR1B1 is associated with significantly low survival of breast cancer patients undergoing chemotherapy; hence, it could be a target for chemo-sensitization and chemo-prevention. Further, in vitro studies showed that AKR1B1 inhibition with NARI-29 has increased the accumulation and sensitized Dox to breast cancer cell lines. However, treatment with NARI-29 has alleviated the Dox-induced toxicity to cardiomyocytes and decreased the secretion of inflammatory cytokines from RAW 264.7 cells. In vivo studies revealed that the NARI-29 (25 and 50 mg/kg) has prevented the functional, histological, biochemical, and molecular alterations induced by Dox treatment. Moreover, we have shown that NARI-29 has prevented the carbonyl reduction of Dox to Doxol in the mouse heart, which reduced the calcium overload, prevented phosphorylation of CaMKII, and reduced the expression of MuRF1 to protect from cardiac injury and apoptosis. Hence in conclusion, AKR1B1 inhibitor NARI-29 could be used as an adjuvant therapeutic agent with Dox to prevent cardiotoxicity and synergize anti-breast cancer activity.

Ephedra Herb extract ameliorates adriamycin-induced nephrotic syndrome in rats via the CAMKK2/AMPK/mTOR signaling pathway.

This study aimed to investigate the effect and mechanisms of Ephedra Herb (EH) extract on adriamycin-induced nephrotic syndrome (NS), providing an experimental basis for the clinical treatment of NS. Hematoxylin and eosin staining, creatinine, urea nitrogen, and kidn injury molecule-1 were used to evaluate the activities of EH extract on renal function. The levels of inflammatory factors and oxidative stress were detected by kits. The levels of reactive oxygen species, immune cells, and apoptosis were measured by flow cytometry. A network pharmacological approach was used to predict the potential targets and mechanisms of EH extract in the treatment of NS. The protein levels of apoptosis-related proteins and CAMKK2, p-CAMKK2, AMPK, p-AMPK, mTOR and p-mTOR in the kidneys were detected by Western blot. The effective material basis of EH extract was screened by MTT assay. The AMPK pathway inhibitor (compound C, CC) was added to investigate the effect of the potent material basis on adriamycin-induced cell injury. EH extract significantly improved renal injury and relieve inflammation, oxidative stress, and apoptosis in rats. Network pharmacology and Western blot results showed that the effect of EH extract on NS may be associated with the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine significantly ameliorated adriamycin-induced NRK-52e cell injury. Methylephedrine also significantly improved the phosphorylation of AMPK and mTOR, which were blocked by CC. In sum, EH extract may ameliorate renal injury via the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine may be one of the material bases of EH extract.

Fisetin attenuates doxorubicin-induced cardiotoxicity by inhibiting the insulin-like growth factor II receptor apoptotic pathway through estrogen receptor-α/-ß activation.

Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX-induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX-induced cell death in a dose-dependent manner. Moreover, western blotting and TUNEL-DAPI staining showed that fisetin significantly attenuated DOX-induced cardiotoxicity in vitro and in vivo by inhibiting the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway through estrogen receptor (ER)-α/-ß activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX-induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX-induced cardiotoxicity.

Influence of Geriatric Nutritional Risk Index on Occurrence of Adverse Events and Duration of Treatment in Patients With Lymphoma Receiving R-CHOP Therapy.

BACKGROUND/AIM: No studies have examined the association between the Geriatric Nutritional Risk Index (GNRI) at the initiation of chemotherapy for malignant lymphoma and the occurrence of adverse events. Therefore, we investigated the impact of GNRI at treatment initiation on the occurrence of side effects and time to treatment failure (TTF) in patients with malignant lymphoma undergoing initial rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. PATIENTS AND METHODS: This study included 131 patients who underwent initial R-CHOP therapy between March 2016 and October 2021. Patients were stratified into those with high (GNRI ≥92; n=56) or low (GNRI <92; n=75) GNRI status. RESULTS: Comparing the High GNRI group and Low GNRI group, the incidence of febrile neutropenia (FN) and Grade ≥3 creatinine increase, alkaline phosphatase (ALP) increase, albumin decrease, hemoglobin decrease, neutropenia, and thrombocytopenia were significantly higher in the Low GNRI group. TTF in the High GNRI group was significantly longer than that in the Low GNRI group (p=0.045). Multivariate analysis showed that the factors influencing the duration of treatment were PS (≥2) at the start of treatment, serum albumin level, and GNRI. CONCLUSION: In patients undergoing R-CHOP therapy, GNRI <92 at regimen initiation increased the risks of developing FN and hematologic toxicity. Multivariate analysis revealed that performance status, albumin levels, and GNRI at regimen initiation were the factors influencing treatment duration. Nutritional status at treatment initiation may influence the development of hematologic toxicity and TTF.

Integrating Network Pharmacology and an Experimental Model to Investigate the Effect of Zhenwu Decoction on Doxorubicin-Induced Heart Failure.

BACKGROUND: Doxorubicin-induced heart failure is a clinical problem that needs to be solved urgently. Previous studies have confirmed that Zhenwu Decoction, a traditional Chinese medicine compound, can effectively improve chronic heart failure. However, its interventional effect on Doxorubicin-induced heart failure has not yet been investigated. In this study, we investigated the therapeutic effect and potential mechanism of Zhenwu Decoction on Doxorubicininduced heart failure through animal experiments and network pharmacology. OBJECTIVE: The study aimed to investigate the therapeutic effect and potential mechanism of Zhenwu Decoction (ZWD) on Doxorubicin-induced heart failure. METHODS: A heart-failure mouse model was established in 8-week-old male C57/BL6J mice using Doxorubicin, and the mice were then treated with ZWD for a 4-week period. Firstly, network pharmacology was conducted to explore the potential active components and molecular mechanisms of ZWD on Doxorubicin-induced heart failure. Next, we conducted an in vivo study on the effect of ZWD on Doxorubicin-induced heart failure. After the intervention, the cardiac function and levels of cardiac function injury marker in serum were measured to evaluate the therapeutic effect of ZWD on cardiac function. Then HE staining and Masson staining were used to evaluate the effect of ZWD on myocardial pathology, and biochemical method was used to detect the effect of ZWD on total antioxidant capacity and inflammation, and finally, Western blot was used to detect TGFß, Smad-3, and collagen I protein expression levels to evaluate its effect on myocardial fibrosis. RESULTS: In Doxorubicin-induced heart failure mice, ZWD improved cardiac function and reduced the levels of CK-MB, NT-proBNP, and BNP in the serum, improved myocardial pathology, and reduced TGFß, Smad-3 and collagen I protein expression levels to improve myocardial fibrosis. Network pharmacological analysis showed that ZWD has 146 active ingredients and 248 candidate targets. Moreover, 2,809 genes were found to be related to Doxorubicin-induced heart failure, and after screening, 74 common targets were obtained, mainly including IL-6, AKT1, caspase-3, PPARG, PTGS2, JUN, HSP90AA1, and ESR1. KEGG analysis confirmed that PI3K/AKT and IL- 6/NF-κB signaling pathways were the two main pathways underlying the cardioprotective effects of ZWD. Finally, in vivo experiments showed that ZWD improved the total antioxidant capacity, reduced the SOD level, increased the protein expression of PI3K, Akt, Bcl-2, Bax, and caspase-3, reduced the levels of TNF-α, IL-6, and IL-1ß, and decreased the NF-κB p65, IL-6, and TNF-α protein expression levels. CONCLUSION: In Doxorubicin-induced heart-failure mice, Zhenwu Decoction improved the cardiac function and myocardial pathology, and improved myocardial fibrosis through the TGFß/Smad-3 signaling pathway. According to the prediction of network pharmacology, in vivo experiments demonstrated that Zhenwu Decoction can improve the oxidative stress response, improve myocardial cell apoptosis through the PI3K/AKT signaling pathway, and improve myocardial inflammation by reducing the levels of inflammatory factors and by reducing the protein expression of NF- κB p65, IL-6, and TNF-α.

Extract of Platycodon grandiflorum Prevents Doxorubicin-induced Cardiotoxicity in Breast Cancer.

Doxorubicin (Dox) is a first-line chemotherapeutic agent applied in cancer treatment. Its long-term anticancer efficacy is restricted mainly due to its subsequent cardiotoxicity for patients. Platycodon grandiflorum (PG), an important traditional Chinese herb, has been reported to eliminate phlegm, relieve cough, and reduce inflammatory diseases. Previous clinical studies found that PG has cardioprotective effects for early breast cancer patients who received Dox-based chemotherapy. However, the cellular and molecular mechanisms underlying PG-mediated cardiotoxic rescue remain elusive. This study aimed to explore the protective role and potential molecular mechanisms of PG on Dox-induced cardiac dysfunction in a mouse model of breast cancer. PG significantly alleviated myocardial damage and prevented cardiomyocyte apoptosis induced by Dox. The expression levels of cytochrome C and cleaved caspase-3 significantly decreased, and the levels of Bcl-XL and B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein increased following PG treatment. Furthermore, PG remarkably enhanced the antimetastatic efficacy (versus the Dox group) by regulating the balance of matrix metalloproteinases/tissue inhibitors of metalloproteinases.

The Safety of Neoadjuvant Therapy with Polyethylene Glycol Liposome Adriamycin Combined with Docetaxel in Patients with Breast Cancer Complicated by Axillary Lymph Node Metastasis.

Objective: To evaluate the safety of the combination of pegylated liposomal doxorubicin and docetaxel in neoadjuvant therapy for breast cancer (BC) with axillary lymph nodes metastasis. Methods: In this single-arm study, 91 patients with clinical stage IIA-IIIc BC received 6 cycles of pegylated liposomal doxorubicin plus docetaxel as neoadjuvant chemotherapy (NAC). Trastuzumab was allowed in patients with human epidermal growth factor receptor 2-positive tumors. The effects of new anthracycline-polyethylene glycol liposomal doxorubicin on the patients' hearts were studied. The changes in left ventricular ejection fraction (LVEF) before and after treatment were evaluated by echocardiography, and the levels of cardiac-specific biomarker troponin I (cTnI) and N terminal B natriuretic peptide (NT-pro-BNP) were noted before and after treatment. Result: In our study, 88 patients completed 6 cycles of neoadjuvant chemotherapy. LVEF was within normal range; average LVEF was 67% at baseline, 66% after NAC. The difference was not statistically significant. However, LVEF decreased by more than 10% in 44.4% of patients. There was no significant difference in troponin I or NT-pro-BNP levels before or after treatment. No cardiac events with clinical symptoms were reported. Conclusion: The combination of polyethylene glycol liposome adriamycin and docetaxel in neoadjuvant chemotherapy in patients with early BC with axillary lymph node metastasis has certain cardiac safety. And in the human epidermal growth factor receptor-2 (HER-2) positive population, polyethylene glycol liposome adriamycin combined with docetaxel and trastuzumab also has certain cardiac safety.

Activation of p62-NRF2 Axis Protects against Doxorubicin-Induced Ferroptosis in Cardiomyocytes: A Novel Role and Molecular Mechanism of Resveratrol.

Doxorubicin (DOX) is a most common anthracycline chemotherapeutic agent; however, its clinical efficacy is limited due to its severe and irreversible cardiotoxicity. Ferroptosis, characterized by iron overload and lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. Resveratrol (RSV) displays cardioprotective and anticancer effects, owing to its antioxidative and anti-inflammatory properties. However, the role and mechanism of RSV in DOX-mediated ferroptosis in cardiomyocytes is unclear. This study showed that DOX decreased cell viability, increased iron accumulation and lipid peroxidation in H9c2 cells; however, these effects were reversed by RSV and ferroptosis inhibitor ferrostatin-1 (Fer-1) pre-treatment. Additionally, RSV significantly increased the cell viability of H9c2 cells treated with ferroptosis inducers Erastin (Era) and RSL3. Mechanistically, RSV inhibited mitochondrial reactive oxygen species (mtROS) overproduction and upregulated the p62-NRF2/HO-1 pathway. RSV-induced NRF2 activation was partially dependent on p62, and the selective inhibition of p62 (using p62-siRNA interference) or NRF2 (using NRF2 specific inhibitor, ML385) significantly abolished the anti-ferroptosis function of RSV. Furthermore, RSV treatment protected mice against DOX-induced cardiotoxicity, including significantly improving left ventricular function, ameliorating myocardial fibrosis and suppressing ferroptosis. Consistent with in vitro results, RSV also upregulated the p62-NRF2/HO-1 expression, which was inhibited by DOX, in the myocardium. Notably, the protective effect of RSV in DOX-mediated ferroptosis was similar to that of Fer-1 in vitro and in vivo. Thus, the p62-NRF2 axis plays a critical role in regulating DOX-induced ferroptosis in cardiomyocytes. RSV as a potent p62 activator has potential as a therapeutic target in preventing DOX-induced cardiotoxicity via ferroptosis modulation.

Mechanisms and Drug Intervention for Doxorubicin-Induced Cardiotoxicity Based on Mitochondrial Bioenergetics.

Doxorubicin (DOX) is an anthracycline chemotherapy drug, which is indispensable in antitumor therapy. However, its subsequent induction of cardiovascular disease (CVD) has become the primary cause of mortality in cancer survivors. Accumulating evidence has demonstrated that cardiac mitochondrial bioenergetics changes have become a significant marker for doxorubicin-induced cardiotoxicity (DIC). Here, we mainly summarize the related mechanisms of DOX-induced cardiac mitochondrial bioenergetics disorders reported in recent years, including mitochondrial substrate metabolism, the mitochondrial respiratory chain, myocardial ATP storage and utilization, and other mechanisms affecting mitochondrial bioenergetics. In addition, intervention for DOX-induced cardiac mitochondrial bioenergetics disorders using chemical drugs and traditional herbal medicine is also summarized, which will provide a comprehensive process to study and develop more appropriate therapeutic strategies for DIC.