Hybrid Liposome-MSN System with Co-Delivering Potential Effective Against Multidrug-Resistant Tumor Targets in Mice Model.

Introduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer. Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects. Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance. Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.

Identification of autophagy-related signatures in doxorubicin-induced cardiotoxicity.

PURPOSE: Doxorubicin is an antibiotic drug used clinically to treat infectious diseases and tumors. Unfortunately, it is cardiotoxic. Autophagy is a cellular self-decomposition process that is essential for maintaining homeostasis in the internal environment. Accordingly, the present study was proposed to characterize the autophagy-related signatures of doxorubicin-induced cardiotoxicity. METHODS: Datasets related to doxorubicin-induced cardiotoxicity were retrieved by searching the GEO database and differentially expressed genes (DEGs) were identified. DEGs were taken to intersect with autophagy-related genes to obtain autophagy-related signatures, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network were performed on them. Further, construction of miRNA-hub gene networks and identification of target drugs to reveal potential molecular mechanisms and therapeutic strategies. Animal models of doxorubicin-induced cardiotoxicity were constructed to validate differences in gene expression for autophagy-related signatures. RESULTS: PBMC and heart samples from the GSE37260 dataset were selected for analysis. There were 995 and 2357 DEGs in PBMC and heart samples, respectively, and they had 23 intersecting genes with autophagy-related genes. RT-qPCR confirmed the differential expression of 23 intersecting genes in doxorubicin-induced cardiotoxicity animal models in general agreement with the bioinformatics results. An autophagy-related signatures consisting of 23 intersecting genes is involved in mediating processes and pathways such as autophagy, oxidative stress, apoptosis, protein ubiquitination and phosphorylation. Moreover, Akt1, Hif1a and Mapk3 are hub genes in autophagy-associated signatures and their upstream miRNAs are mainly rno-miR-1188-5p, rno-miR-150-3p and rno-miR-326-3p, and their drugs are mainly CHEMBL55802, Carboxyamidotriazole and 3-methyladenine. CONCLUSION: This study identifies for the first-time autophagy-related signatures in doxorubicin's cardiotoxicity, which could provide potential molecular mechanisms and therapeutic strategies for doxorubicin-induced cardiotoxicity.

Microbubbles bound to drug-eluting beads enable ultrasound imaging and enhanced delivery of therapeutics.

Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0-37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70-150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control.

The protective effect of Ghrelin peptide on doxorubicin hydrochloride induced heart failure in rats.

BACKGROUND: To investigate the protective effect and mechanism of Ghrelin on Doxorubicin (Dox) hydrochloride induced heart failure (HF) and myocardial injury in rats. METHODS: 45 rats were randomly divided into control group, HF group and Ghrelin group. Dox hydrochloride was injected intraperitoneally to establish the model of HF in rats of HF group and Ghrelin group. Rats in the Ghrelin group were given intraperitoneal injection of Ghrelin twice a day, and rats in the HF group and control group were given equal volume of normal saline for a total of 6 weeks. The changes of echocardiography, cardiac hemodynamics, myocardial histology and plasma inflammatory factors were observed. RESULTS: After the Ghrelin intervention, compared with the HF group, the left ventricular end-diastolic diameter (LVDD) and left ventricular end-systolic diameter (LVSD) in the Ghrelin group was markedly reduced (P < 0.05), and left ventricular ejection fraction (LVEF) was significantly increased (P < 0.05). Compared with HF group, the left ventricular systolic pressure (LVSP), maximum rate of increase in left ventricular pressure (+ dP/dtmax) and maximum rate of decrease in left ventricular pressure (- dP/dtmax) of Ghrelin group was remarkedly increased (P < 0.05), left ventricular diastolic pressure (LVDP) decreased (P < 0.05). In the Ghrelin group, the degree and extent of cardiomyocyte degeneration and necrosis were remarkedly reduced compared with the HF group. The levels of TNF-α and iNOS in Ghrelin group were notably lower than those in HF group (P < 0.05), the IL-10 level increased markedly (P < 0.05). CONCLUSION: Ghrelin may reduce Dox-induced myocardial injury and improve cardiac function in rats by regulating inflammation and oxidative stress.

Analysis of doxorubicin and fullerenol in rat serum by micellar electrokinetic capillary chromatography.

A new micellar electrokinetic capillary chromatographic (MEKC) method has been developed and optimized for simultaneous quantitation of doxorubicin (Dox) and fullerenol (Frl) in rat serum. The separation was carried out in a capillary (48.5-40 cm to the detector - 50 µm id fused-silica capillary with bubble cell, 150 µm) at an applied voltage of 25 kV and temperature of 25 °C. For the background electrolyte 10 mmol L- 1 borate buffer pH 9.3 plus 15 mmol L-1 phosphate buffer pH 7.0 (with the final pH of the mixture adjusted to 7.0 with HCl), with added 10 % (V/V) methanol, and 15 mmol L-1 sodium dodecyl sulfate as a surfactant, were used. The hydrodynamic injection was carried out at 5.0 kPa during the period of 100 s. Linear calibration curves were established over the concentration range 0.5-500.0 mg L- 1 for Dox and 10.0-500.0 mg L- 1 for Frl (at 234 nm). The proposed MEKC procedure was fully validated and applied for the deter mination of Dox and Frl in Wistar rats after intra pe ritoneal administration of both molecules.

Acoustic Controllable Spatiotemporal Cell Micro-oscillation for Noninvasive Intracellular Drug Delivery.

Intracellular cargo delivery is crucial for drug evaluation, nanomedicine development, and gene therapy, in which high efficiency while maintaining cell viability is needed for downstream analysis. Here, an acoustic-mediated precise drug delivering mechanism is proposed by directly modulating cell micro-oscillation mode and membrane permeability. Through phase shifting keying-based spatiotemporal acoustic tweezers, controllable oscillating cell arrays can be achieved in shaking potentials. At the same time, continually oscillating radiation force and fluid shear stress exerted on cells effectively disturbs cellular membrane mobility and enhances permeability, thereby facilitating nanodrug entrance. In experiments, cell oscillation is tunable in frequency (10-2 to 102 Hz), shaking direction, amplitude (0 to quarter acoustic wavelength), and speed. Doxorubicin is actively delivered across cellular membranes and accumulates in inner cells, with a concentration more than 8 times that of the control group. Moreover, there is no obvious compromise in cell activity during oscillation, exhibiting excellent biocompatibility. This "dancing acoustic waves" scheme introduces a new dimension of cell manipulation in both space and time domains and an effective drug delivering strategy, offering advantages of flexibility, gentleness, and high throughput. It may advance related fields like nanobiological research, drug and nanomedicine development, and medical treatment.

Influence of Redox-Active Chitosan-Polyaminoxyl Micelles Loaded with Daunorubicin on Activity of Nrf2 Transcription Factor.

A new system for delivery of anthracycline antibiotics based on chitosan-polyaminoxyls (CPA) was studied in a model of non-tumor (human embryonic mesenchymal stem cells) and tumor cells (human hepatocellular carcinoma) in vitro. The presence of CPA micelles considerably suppresses daunorubicin-induced ROS generation in normal cells without affecting this process in tumor cells. CPA micelles do not reduce the cytotoxic effect of daunorubicin and do not prevent its accumulation in cells. The use of CPA significantly increases accumulation of Nrf2 transcription factor in the nuclei of both normal and tumor cells in comparison with free daunorubicin. Increased nuclear translocation of Nrf2 leads to a significant increase in the expression of its target gene TXN1, but not the NQO1, GPX1, and HMOX1 genes, the increased expression of which can lead to the development of resistance to anthracycline antibiotics. Redox-active CPA micelles have great potential for the development of nanoparticles for the transport of anthracycline antibiotics in experimental tumor chemotherapy, and also as promising activators of Nrf2 transcription factor.

Nanocarrier-based drug delivery system with dual targeting and NIR/pH response for synergistic treatment of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.

The protective effects of esculetin against Doxorubicin-Induced hepatotoxicity in rats: Insights into the modulation of Caspase, FOXOs, and heat shock protein pathways.

Doxorubicin (DOX) is an anthracycline antibiotic widely employed to treat carcinoma. Nevertheless, severe cardiotoxic side effects restrict its clinical use. Esculetin, a natural flavonoid, is found abundantly in plants. This study evaluated the protective effects of esculetin against DOX-induced hepatotoxicity in rat livers. Forty-eight rats were randomly divided into six groups with eight rats in each group: control (I), DOX (II), esculetin (III, 50 mg/kg), esculetin (IV, 100 mg/kg), DOX+esculetin 50 (V, DOX+esculetin 50 mg/kg), and DOX+esculetin 100 (VI, DOX+esculetin 100 mg/kg). The administration of esculetin effectively mitigated alterations in the measured biochemical parameters induced by DOX. Gene expression analyses demonstrated that esculetin treatment significantly reduced the DOX-induced expression of Foxo1, Hspa1a, Hsp4a, Hsp5a, Casp3, and Casp9 while increasing the DOX-induced expression of Foxo3. These findings suggest that esculetin, with its antioxidant and anti-inflammatory effects, might be a therapeutic option for protecting against DOX-induced hepatotoxicity.

Combined Chemo- and Photothermal Therapies of Non-Small Cell Lung Cancer Using Polydopamine/Au Hollow Nanospheres Loaded with Doxorubicin.

Purpose: The chemotherapeutic agent doxorubicin (DOX) is limited by its cardiotoxicity, posing challenges in its application for non-small cell lung cancer (NSCLC). This study aims to explore the efficacy of polydopamine/Au nanoparticles loaded with DOX for chemotherapy and photothermal therapy in NSCLC to achieve enhanced efficacy and reduced toxicity. Methods: Hollow polydopamine (HPDA)/Au@DOX was synthesized via polydopamine chemical binding sacrificial template method. Morphology was characterized using transmission electron microscopy, particle size and potential were determined using dynamic light scattering, and photothermal conversion efficiency was assessed using near-infrared (NIR) thermal imaging. Drug loading rate and in vitro drug release were investigated. In vitro, anti-tumor experiments were conducted using CCK-8 assay, flow cytometry, and live/dead cell staining to evaluate the cytotoxicity of HPDA/Au@DOX on A549 cells. Uptake of HPDA/Au@DOX by A549 cells was detected using the intrinsic fluorescence of DOX. The in vivo anti-metastasis and anti-tumor effects of HPDA/Au@DOX were explored in mouse lung metastasis and subcutaneous tumor models, respectively. Results: HPDA/Au@DOX with a particle size of (164.26±3.25) nm, a drug loading rate of 36.31%, and an encapsulation efficiency of 90.78% was successfully prepared. Under 808 nm laser irradiation, HPDA/Au@DOX accelerated DOX release and enhanced uptake by A549 cells. In vitro photothermal performance assessment showed excellent photothermal conversion capability and stability of HPDA/Au@DOX under NIR laser irradiation. Both in vitro and in vivo experiments demonstrated that the photothermal-chemotherapy combination group (HPDA/Au@DOX+NIR) exhibited stronger anti-metastatic and anti-tumor activities compared to the monotherapy group (DOX). Conclusion: HPDA/Au@DOX nanosystem demonstrated excellent photothermal effect, inhibiting the growth and metastasis of A549 cells. This nanosystem achieves the combined effect of chemotherapy and photothermal, making it promising for NSCLC treatment.

Precision Treatment of Colon Cancer Using Doxorubicin-Loaded Metal-Organic-Framework-Coated Magnetic Nanoparticles.

Due to the limited efficacy and evident side effects of traditional chemotherapy drugs attributed to their lack of specificity and selectivity, novel strategies are essential for improving cancer treatment outcomes. Here, we successfully engineered Fe3O4 magnetic nanoparticles coated with zeolitic imidazolate framework-8 (ZIF-8). The resulting nanocomposite (Fe3O4@ZIF-8) demonstrates efficient adsorption of a substantial amount of doxorubicin (DOX) due to the porous nature of ZIF-8. The drug-loaded nanoparticles, Fe3O4@ZIF-8/DOX, exhibit significant accumulation at the tumor site in SW620 colon-cancer-bearing mice when guided by an external magnetic field. Within the acidic microenvironment of the tumor, the ZIF-8 framework collapses, releasing DOX and effectively inducing tumor cell death, thereby inhibiting cancer progression while not causing undesired side effects, as confirmed by a variety of in vitro and in vivo characterizations. In comparison to free DOX, Fe3O4@ZIF-8/DOX nanoparticles show superior efficacy in colon cancer treatment. Our findings suggest that Fe3O4@ZIF-8 holds promise as a carrier for small-molecule drug adsorption and its ferromagnetic properties provide drug targeting capabilities, thereby enhancing therapeutic effects on tumors at the same drug dosage. With excellent biocompatibility, Fe3O4@ZIF-8 demonstrates potential as a drug carrier in targeted cancer chemotherapy. Our work suggests that a combination of magnetic targeting and acid-responsiveness holds great promise for advancing targeted cancer therapy in precision nanomedicine.

Synergy between isobavachalcone and doxorubicin suppressed the progression of anaplastic thyroid cancer through ferroptosis activation.

The objective of this study was to explore the effects and mechanisms of the combination of isobavachalcone (IBC) and doxorubicin (DOX) on the progression of anaplastic thyroid cancer (ATC). Cell viability of 8505C and CAL62 cells was observed by CCK-8 assay. Kits were used to detect the presence of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and cellular iron. Protein expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was detected using western blot, and CD31 was detected through immunofluorescence. Tumor xenograft models of 8505C cells were constructed to observe the effect of IBC and DOX on ATC growth in vivo. The co-administration of IBC and DOX exhibited a synergistic effect of suppressing the growth of 8505C and CAL62 cells. The concurrent use of IBC and DOX resulted in elevated iron, ROS, and MDA levels, while reducing GSH levels and protein expression of SLC7A11 and GPX4. However, the Fer-1 ferroptosis inhibitor effectively counteracted this effect. In vitro and in vivo, the inhibitory effect on ATC cell proliferation and tumor growth was significantly enhanced by the combination of IBC and DOX. The combination of IBC and DOX can inhibit the growth of ATC by activating ferroptosis, and might prove to be a potent chemotherapy protocol for addressing ATC.

Prophylactic impacts of Lagenaria siceraria against cardiomyopathy induced by doxorubicin in a rat model.

Background: Doxorubicin (DOX) is a chemotherapeutic drug applied clinically for the remedy of cancer, but its possibly life-threatening cardiotoxicity effects remain a concern. Aim: After that, this study evaluates the cardioprotective impacts of Lagenaria siceraria (LSS) oil on DOX induced cardiomyopathy in rats. Methods: Wistar male rats (n = 28, weighting 190-210 g) were arbitrarily allocated into four equal groups. Group 1 control group (CTR) received normal saline orally (1 ml/kg); group 2 (DOX) received DOX (10 mg/kg); group 3 (DOLS) received DOX + 3 g of Lagenaria siceraria seeds oil/kg; group 4 (LSSO) received LSSO (3 g/kg) daily for 18 days. The serum samples were collected to determine the creatine kinase-MB (CK-MB) isoenzyme, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and Troponin I activity. At the same time, the catalase, malondialdehyde (MDA), and reduced glutathione (GSH) were assessed in heart tissues. Additionally, histopathological investigations for the heart tissue were performed. Results: Results revealed no significant change in CK-MB levels between the DOLS group compared to the CTR group (p > 0.05). DOX group confirmed a substantial increase in AST, LDH, and Troponin1 serum levels compared to DOLS and LLSO groups (p < 0.05). The study demonstrated the antioxidant activity of LSS oil against DOX-induced toxicity. The DOX group significantly reduced GSH and catalase levels, with an increase in MDA levels compared to DOLS and LLSO groups. Histopathological analysis showed protective properties of LSS oil against myocardial damage caused by DOX. Conclusion: This study highlights the favorable impacts of LSS oil in mitigating DOX-triggered cardiotoxicity in a rat model.

Doxorubicin-related cardiotoxicity: review of fundamental pathways of cardiovascular system injury.

Over the years, advancements in the field of oncology have made remarkable strides in enhancing the efficacy of medical care for patients with cancer. These modernizations have resulted in prolonged survival and improved the quality of life for these patients. However, this progress has also been accompanied by escalation in mortality rates associated with anthracycline chemotherapy. Anthracyclines, which are known for their potent antitumor properties, are notorious for their substantial cardiotoxic potential. Remarkably, even after 6 decades of research, a conclusive solution to protect the cardiovascular system against doxorubicin-induced damage has not yet been established. A comprehensive understanding of the pathophysiological processes driving cardiotoxicity combined with targeted research is crucial for developing innovative cardioprotective strategies. This review seeks to explain the mechanisms responsible for structural and functional alterations in doxorubicin-induced cardiomyopathy.

Interrogating the Role of Endocytosis Pathway and Organelle Trafficking for Doxorubicin-Based Combination Ionic Nanomedicines.

We have studied the endocytic mechanisms that determine subcellular localization for three carrier-free chemotherapeutic-photothermal (chemo-PTT) combination ionic nanomedicines (INMs) composed of doxorubicin (DOX) and an near-infrared (NIR) dye (ICG, IR820, or IR783). This study aims to understand the cellular basis for previously published enhanced toxicity results of these combination nanomedicines toward MCF-7 breast cancer cells. The active transport mechanism of INMs, unlike free DOX, which is known to employ passive transport, was validated by conducting temperature-dependent cellular uptake of the drug in MCF-7 cells using confocal microscopy. The internalization pathway of these INMs was further probed in the presence and absence of different endocytosis inhibitors. Detailed examination of the mode of entry of the carrier-free INMs in MCF-7 cells revealed that they are primarily internalized through clathrin-mediated endocytosis. In addition, time-dependent subcellular localization studies were also investigated. Examination of time-dependent confocal images indicated that the INMs targeted multiple organelles, in contrast to free DOX that primarily targets the nucleus. Collectively, the high cellular endocytic uptake in cancerous cells (EPR effect) and the multimode targeting ability demonstrated the main reason for the low half-maxima inhibitory concentration (IC50) value (the high cytotoxicity) of these carrier-free INMs as compared to their respective parent chemo and PTT drugs.

Doxorubicin downregulates cell cycle regulatory hub genes in breast cancer cells.

Breast cancer (BC) is the leading commonly diagnosed cancer in the world, with complex mechanisms underlying its development. There is an urgent need to enlighten key genes as potential therapeutic targets crucial to advancing BC treatment. This study sought to investigate the influence of doxorubicin (DOX) on identified key genes consistent across numerous BC datasets obtained through bioinformatic analysis. To date, a meta-analysis of publicly available coding datasets for expression profiling by array from the Gene Expression Omnibus (GEO) has been carried out. Differentially Expressed Genes (DEGs) identified using GEO2R revealed a total of 23 common DEGs, including nine upregulated genes and 14 downregulated genes among the datasets of three platforms (GPL570, GPL6244, and GPL17586), and the commonly upregulated DEGs, showed significant enrichment in the cell cycle in KEGG analysis. The top nine genes, NUSAP1, CENPF, TPX2, PRC1, ANLN, BUB1B, AURKA, CCNB2, and CDK-1, with higher degree values and MCODE scores in the cytoscape program, were regarded as hub genes. The hub genes were activated in disease states commonly across all the subclasses of BC and correlated with the unfavorable overall survival of BC patients, as verified by the GEPIA and UALCAN databases. qRT-PCR confirmed that DOX treatment resulted in reduced expression of these genes in BC cell lines, which reinforces the evidence that DOX remains an effective drug for BC and suggests that developing modified formulations of doxorubicin to reduce toxicity and resistance, could enhance its efficacy as an effective therapeutic option for BC.

Myocardium-targeted liposomal delivery of the antioxidant peptide 8P against doxorubicin-induced myocardial injury.

Doxorubicin (Dox) is a broad-spectrum antineoplastic chemotherapeutic agent used in clinical settings, yet it exhibits significant cardiotoxicity, which in severe cases can lead to heart failure. Research indicates that oxidative stress plays a pivotal role in Dox -induced cardiomyocyte injury. Therefore, the application of antioxidants represents an effective strategy to mitigate the cardiotoxic effects of doxorubicin. In preliminary studies, we isolated an antioxidative peptide, PHWWEYRR (8P). This study utilizes a PCM cardiomyocyte-targeting peptide-modified liposome as a carrier to deliver 8P into cardiomyocytes, aiming to prevent Dox-induced cardiac injury through its antioxidative mechanism. The results demonstrated that we prepared the 8P-loaded and PCM-targeting peptide-modified liposome (P-P-8P), which exhibited good dispersibility, encapsulation efficiency, drug loading capacity, and in vitro release, along with myocardial targeting capability. In vitro experiments showed that P-P-8P could prevent oxidative stress injury in H9C2 cells, protect mitochondrial functions, and inhibit cell apoptosis through a mitochondria-dependent pathway. In vivo experiments indicated that P-P-8P could prevent abnormalities in serum biochemical indicators, cardiac dysfunction, and myocardial pathological changes in mice. In conclusion, P-P-8P effectively delivers 8P to cardiomyocytes, offering protection against the cardiotoxic effects of Dox, and holds potential as a future preventative or therapeutic agent for drug-induced cardiomyopathy.

Melatonin and Metformin Mitigate Doxorubicin-Induced Alveolar Bone Toxicity.

Evidence concerning the osteotoxic effects of chemotherapy (doxorubicin) has been previously described. Periodontitis also progressively increases in patients receiving chemotherapy; however, the beneficial effects of melatonin and metformin on the alleviation of doxorubicin-induced osteotoxicity have never been investigated. Therefore, we investigated the negative impact of doxorubicin on alveolar bone homeostasis and the benefits of melatonin and metformin on the attenuation of doxorubicin-induced alveolar bone toxicity. Male Wistar rats were divided into 4 groups to receive either 1 mL of normal saline solution as a control group, 3 mg/kg of doxorubicin, 3 mg/kg of doxorubicin plus 10 mg/kg of melatonin, or 3 mg/kg of doxorubicin plus 250 mg/kg of metformin. Doxorubicin treatment was given on days 0, 4, 8, 15, 22, and 29, while interventions were given daily on days 0 to 29. Following euthanasia, blood and alveolar bones were collected for evaluation of oxidative stress, bone remodeling, inflammation, microarchitecture, and periodontal condition. We found that doxorubicin increased systemic oxidative stress, decreased antioxidative capacity, increased inflammation, decreased bone formation, increased bone reabsorption, impaired microarchitecture, and impaired periodontal condition of the alveolar bone. Although cotreatment with melatonin or metformin resulted in some improvement in these parameters, cotreatment with melatonin was more effective than cotreatment with metformin in terms of decreasing oxidative stress, reducing bone resorption, and improving microarchitecture and periodontal condition. All of these findings highlight the potential for antioxidants, especially melatonin, to ameliorate doxorubicin-induced alveolar bone toxicity.