الفهرس 
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Abstract
Doxorubicin is a broad-spectrum antitumor and antibiotic that is used to treat cancer patients. Doxorubicin treatment has resulted in cardiac injury and organ toxicity in humans and laboratory animals. The current study aimed to study their protective effect of QU and QU-CHSNPs against DOX-induced cardiotoxicity in male Wister rats.
In the current study, thirty rats were used. These rats were divided into five groups (n = 6) as follows:
group 1: (Control group): Normal healthy rats were supplemented with the equivalent volume of 0.9% NaCl (2ml/kg, three times per week) for six weeks by oral gavage.
group 2 (Doxorubicin–administered control): To cause cardiotoxicity, the rats were given six doses of 1.25 mg/kg/48h of DOX intraperitoneally (i.p.r) over the course of two weeks.
group 3 (Doxorubicin-administered group treated with QU natural): The rats in this group received six consecutives I.P. injections of doxorubicin at a dose level of 1.25 mg/kg/48 hours over the course of two weeks. On the same day that DOX began, QU natural form that was suspended in a 0.9% NaCl saline solution (10 mg/kg, three times per week, orally) was also begun and continued for a further 4 weeks after DOX was stopped (6-week total period).
group 4 (Doxorubicin-administered group treated with QU-CHSNPs): The rats in this group received six consecutives I.P. injections of doxorubicin at a dose level of 1.25 mg/kg/48 hours over a two-week period. On the same day that DOX began being administered, QU-CHSNPs (10 mg/kg, three times per week, orally) began being administered concurrently. QU-CHSNPs continued to be administered for a further four weeks after DOX was stopped (6-week total period).
group 5 (Normal group treated with QU-CHSNPs): QU-CHSNPs (10 mg/kg, three times per week) was administered orally to healthy normal rats for a period of six weeks.
By the end of the experiment, six animals from each group had been sacrificed under mild diethyl ether anesthesia. Blood samples from each rat were drawn, allowed to coagulate, and then centrifuged. The clear supernatant serum was quickly removed for biochemical analysis, which included measuring heart function parameters in the serum (CK-MB, AST, LDH, and c Tn-I), liver functions (ALT and GGT), kidney functions (creatinine and urea), serum lipid profile (T. Cholesterol, TG, LDL-c, VLDL-c, and HDL-c), serum pro-inflammatory cytokine (TNF-α and IL-1B), anti-inflammatory cytokine (IL-10), Serum apoptotic marker Caspase-3.
After the animals had been dissected, tissues from the heart, liver and kidney were quickly removed. Part of fresh heart samples were stored at -20◦C to be used for determination of cardiac DNA fragmentation by gel electrophoresis. Part of the cardiac tissues were placed in RNA latter for analysis of molecular parameters (cardiac mRNA gene expressions NrF2, PPAR-γ and Annexin-V). The remaining part of heart was fixed in 3% glutaraldehyde and examined using a transmission electronic microscope. 0.5g from heart, liver, and kidney tissue samples were homogenized to determine LPO product, NO, and antioxidant enzyme activity, such as GSH content, GST, GPX, and SOD. The remaining parts of heart, liver, and kidney tissue samples were fixed in 10% neutral buffered formalin and examined using a light microscope for histopathological examination.
Additionally, the prepared QU-CHSNPs and CHSNPs was characterized using XRD, FTIR, Zeta potential and Zeta sizer, Entrapment efficiency, quercetin release, High-resolution transmission electron microscopy (HR-TEM) and Scanning electron microscope (SEM).
The results demonstrated that doxorubicin significantly increased the serum enzyme activities of cardiac function parameters (CK-MB, AST, LDH, and c Tn-I). Additionally, doxorubicin significantly increased the levels of the serum enzymes liver function parameters (ALT and GGT), kidney function parameters (creatinine and urea), serum lipid profile (T. Cholesterol, TG, LDL-c, VLDL-c), serum IL-1B, TNF-α and Caspas-3 while significantly lowering the levels of serum IL-10 and HDL-c.
It has been shown that doxorubicin administration significantly increased the activity of MDA and NO activity while decreasing the levels of glutathione-S-transferase, superoxide-dismutase, glutathione content, and glutathione peroxidase. Doxorubicin caused a marked elevation in annexin-V and DNA fragmentation while it caused a marked decrease in level of NrF2, PPAR-γ.
These biochemical alterations in the doxorubicin-treated rats are supported by TME alterations in the heart, where DOX inhibits mitochondrial fusion, promotes mitochondrial fission, and impairs mitochondrial function, leading to heart failure. The mitochondrial determinants of DOX cardiotoxicity were studied in this study, and the findings revealed that the mitochondria’s size, shape, and integrity were lost.
Histopathological changes in the heart, which show severe degenerative changes and necrosis of cardiac muscles along with focal lymphocytic infiltration, confirm these biochemical changes of doxorubicin-administered rats.
Also, doxorubicin-induced hepatotoxicity was evidenced by severe histological changes including marked congestion in the central veins and blood vessels of portal area and severe necrotic changes. Meanwhile, pyknotic changes in some hepatocytes, lymphocytic infiltration and cytoplasmic vacuolation.
Additionally, histological changes such as severe degenerative changes linked to nuclear pyknosis of the renal lining epithelium and severe glomerulonephosis were evidence of doxorubicin-induced nephrotoxicity.
The treatment of doxorubicin-administered rats with QU and QU-CHSNPs significantly ameliorated the harmful effect of doxorubicin on serum enzyme activities of heart function parameters (CK-MB, AST, LDH, and c Tn-I). The elevated liver function enzymes as a result of administration of doxorubicin were decreased due to treatment with QU and QU-CHSNPs. The elevated kidney function parameters (creatinine and urea) due to administration of doxorubicin were decreased due to treatment with QU and QU-CHSNPs.
The treatment of doxorubicin-treated rats with QU and QU-CHSNPs resulted in a significant decrease in serum lipid profile (serum cholesterol, triglyceride, low density lipoprotein cholesterol, and very low-density lipoprotein cholesterol) and a significant increase in high density lipoprotein cholesterol.
In addition, QU and QU-CHSNPs treatment of doxorubicin-treated rats reduced the increased levels of serum tumor necrosis factor-alpha, interleukin-1B, and Caspas-3 while increasing the level of serum interleukin-10, indicating their anti-inflammatory properties.
Treatment with QU and QU-CHSNPs reduced the content of MDA and NO product while increasing glutathione-S-transferase, superoxide-dismutase, glutathione content, and glutathione peroxidase levels in the heart, liver, and kidney. As a result, these treatments have the potential to improve the antioxidant system and reduce oxidative stress.
The administration of QU and QU-CHSNPs to doxorubicin-treated rats improved cardiac decreases in NrF2, PPAR-γ, and elevations in annexin-V and DNA fragmentation.
The treatment of doxorubicin-administered rats with QU and QU-CHSNPs ameliorate the histopathological changes caused in heart, liver and kidney tissue and TME alterations in the heart due to administration of doxorubicin.
Additionally, it has been shown that quercetin, after being analyzed, has a number of positive effects on human health, including cardiovascular protection, antioxidant, anti-cancer, anti-viral, anti-allergic, anti-oxidative, and anti-inflammatory activity. These findings suggest that QU and QU-CHSNPs may be able to prevent the cardio, hepato-, and renal toxicity caused by doxorubicin. The cardiac glutathione content and antioxidant activities may play an important role in the protection against doxorubicin-induced toxicity. Furthermore, the anti-inflammatory, antioxidant, and anti-apoptotic effects of QU and QU-CHSNPs may be important in protecting against doxorubicin-induced toxicity.
However, additional clinical studies are needed to assess the safety, benefits and hazards of QU and QU-CHSNPs in humans.