Primary Protection of Diosmin Against Doxorubicin Cardiotoxicity via Inhibiting Oxido-Inflammatory Stress and Apoptosis in Rats.

Doxorubicin (DOX) is the cornerstone of chemotherapy. However, it has dose-dependent cardiotoxic events that limit its clinical use. This study was intended to investigate the efficiency of DOX as an anti-cancer against the MCF-7 cell line in the presence of diosmin (DIO) and to appraise the protective impact of DIO against DOX cardiotoxicity in vivo. In vitro study was carried out to establish the conservation of DOX cytotoxicity in the presence of DIO. In vivo study was conducted on 42 adult female Wistar rats that were equally allocated into 6 groups; control, DIO (100 mg/kg), DIO (200 mg/kg), DOX (20 mg/kg, single dose i.p.), DIO (100 mg/kg) + DOX, received DIO orally (100 mg/kg) for 30 days, then administrated with a single dose of DOX and DIO (200 mg/kg) + DOX, received DIO orally (200 mg/kg) for 30 days, then administrated with DOX. In vitro study showed preservation of cytotoxic activity of DOX on MCF-7 in the presence of DIO. In vivo study indicated that DOX altered electrocardiograph (ECG) parameters. Also, it yielded a significant rise in CK-MB, cTnT and LDH serum levels and cardiac contents of MDA, IL-1ß; paralleled by a significant drop in cardiac IL-10 and SOD. Moreover, significant upregulation of Bax, TNF-α, and HIF-1α, in concomitant with significant downregulation of Bcl-2 mRNA in cardiac tissue have been recorded in the DOX group. Furthermore, histopathological description of cardiac tissues showed that DOX alters normal cardiac histoarchitecture. On the opposite side, DIO pretreatment could ameliorate ECG parameters, suppress IL-1ß and enhanceIL-10, promote activity of SOD and repress MDA. Additionally, downregulation of Bax, TNF-α, HIF-1α and upregulation of Bcl-2 have been demonstrated in DIO-pretreated rats. Furthermore, the histopathological examination of cardiac tissues illustrated that DIO had a favorable impact on the protection of heart histoarchitecture. DIO is suggested for protection against acute cardiotoxicity caused by DOX without affecting antitumor activity.

Combined effects of naringin and doxorubicin on the JAK/STAT signaling pathway reduce the development and spread of breast cancer cells.

Breast cancer therapy options are limited due to its late diagnosis and poor prognosis. Doxorubicin is the fundamental therapy approach for this disease. Because chemotherapy has numerous adverse effects, the scope of the existing research was to appraise the synergetic effect of doxorubicin and naringin and explore the underlying mechanism. The cytotoxicity of doxorubicin and naringin on MCF-7 was monitored. Furthermore, the expression of STAT3 and JAK1 as well as the apoptotic and metastatic related genes (Bax, Bcl-2, Survivin, and VEGF) were conducted by immunoblotting assay and qRT-PCR. In addition, a wound healing test was utilized to appraise the migration and metastasis of MCF-7. Our results revealed that naringin and doxorubicin had a synergetic inhibitory influence on MCF-7 cells growth and migration. The synergetic action of doxorubicin and naringin effectively hindered the expression of STAT3, JAK1, Bcl-2, Survivin, and VEGF, with a boost in the level of Bax compared to cells treated with either doxorubicin or naringin. In conclusion, our findings imply that combining doxorubicin with naringin may be a favorable strategy for inhibiting the growth of breast cancer.

Inhibition of Drp1 orchestrates the responsiveness of breast cancer cells to paclitaxel but insignificantly relieves paclitaxel-related ovarian damage in mice.

Chemoresistance and chemotherapy-related ovarian damage are well-reported in breast cancer (BC) young patients. Herein, the inhibition of the mitochondrial fission was invested to explore its chemosensitizing role in Paclitaxel (PTX)-resistant cells, and its ability to restore the ovarian integrity in mice receiving PTX or cisplatin chemotherapy. To establish these aims, PTX-resistance was generated in BC cells, which were treated with PTX in combination with Drp1 deficiency, via mdivi-1, or Drp1-specific siRNA transfection. Furthermore, the alterations in the ovarian structure and the endocrine-related hormones were explored in mice receiving repetitive doses of PTX or cisplatin. We found that combining PTX with mdivi-1 improved cell responsiveness to PTX, induced apoptosis- and autophagy-mediated cell death, and relieved cellular oxidative stress. Additionally, the expression of PCNA1 and cyclin B1 genes were downregulated, meanwhile, p53, p21, and mitochondrial fusion proteins (Mfu1&Mfu2) were increased. The in vivo investigations in mice demonstrated that PTX induced gonadotoxic damage similar to cisplatin, whereas dual treatment of mice with PTX+ mdivi-1 failed to restore their normal follicular count and the circulating levels of E2 and AMH hormones. These results suggested that combining Drp1 inhibition with PTX resensitized breast cancer cells to PTX but failed to offer enough protection against chemotherapy-related gonadotoxicity.

A Licorice Roots Extract Induces Apoptosis and Cell Cycle Arrest and Improves Metabolism via Regulating MiRNAs in Liver Cancer Cells.

Targeting altered metabolism in cancer provides a promising preventive and therapeutic approach. Natural products interplay between gene expression and metabolism either by targeting altered metabolic enzymes and/or affecting the regulating miRNAs. Licorice is a widely known product used as flavoring agent. Glycyrrhizin and other metabolites were reported to exert several metabolic benefits. Here, we investigated the effect of licorice roots extract on some metabolic pathways and their regulating miRNAs in hepatocellular carcinoma cells. Our data showed various beneficial effects of licorice roots extract including induction of apoptosis and cell cycle arrest. Second, upregulating tumor suppressor miRNAs; let7a-3p, miR-34c-5p, miR-122-5p, miR-126-3p, miR195-5p, miR-199a-5p, miR-206, and miR-326-5p. Third, inhibiting HIF1α, PI3K and C-Myc and activating AMPK and p53. Fourth, inhibiting enzymes of glycolysis; HK-2, LDH-A and PK-M2; pentose phosphate pathway; G6PD and glutaminolysis; glutaminase. However, such an extract upregulated oncogenic miRNAs; miR-21, miR-221, and miR-222. Although the present data highlights the ability of licorice roots extract to enhance apoptosis and cell cycle arrest and correct altered metabolism, it warns against its unfavorable effects, hence, its use for prevention and therapy should proceed with caution. Further experiments are required to investigate whether a specific bioactive ingredient is responsible for upregulating the oncogenic miRNAs.

Circulating MiR-210 and MiR-1246 as Potential Biomarkers for Differentiating Hepatocellular Carcinoma from Metastatic Tumors in the Liver.

BACKGROUND: To date few reports have pointed out the role of circulating miRNAs in discriminating metastatic liver tumors from primary hepatocellular (HCC) tumors. Such discrimination will have significant therapeutic and prognostic implications. The purpose of this study was to evaluate the potential value of a panel of HCC-related circulating miRNAs (miR-142, miR-182, miR-200a, mir-210, miR-211, miR-302b, miR-324, miR-338, miR-340 and miR-1246) as noninvasive biomarkers for discriminating primary HCC from metastatic tumors in the liver. METHODS: The expression level of the selected miRNAs was quantified by quantitative real time PCR in 33 patients with HCC, 22 patients with metastatic tumors in the liver, and 30 healthy volunteers as control. Mann-Whitney U test was used to evaluate the difference in miRNAs expression between primary and metastatic liver tumors and to study the associations between their relative expression levels and the clinicopathological factors. Receiver operating characteristic curve was used to evaluate the diagnostic value of the individual miRNAs. RESULTS: Statistical analyses revealed a differential expression in the level of serum miR-210 and miR-1246 between the two groups of patients. The sensitivity and specificity of miR-210, for differentiating HCC from metastatic malignancies in the liver were found to be 73.7% and 64.28%, respectively. Whilst, of miR-1246 were 72.2% and 67.8%, respectively. In addition, the differential expression of the two miRNAs was also found to be associated with clinicopathological parameters in the two studied groups. CONCLUSIONS: Serum miR-210 and miR-1246 have some diagnostic value for discriminating patients with metastatic tumors to patients with primary HCC.

Circulating microRNAs as predictive biomarkers for liver disease progression of chronic hepatitis C (genotype-4) Egyptian patients.

Egypt is one of the highest prevalence rates of hepatitis C virus (HCV) infection worldwide. HCV is among major reasons for chronic liver diseases. MicroRNA (miRNAs), small noncoding regulatory molecules play a key role in the pathogenesis of liver. Circulating miRNAs represent potential noninvasive biomarkers for diagnosis and monitoring patients with liver diseases progression. To investigate the potential role of circulating miRNAs for surveillance of liver disease progression, we assessed the expression of 20 liver-related miRNAs in sera of 47 chronic hepatitis C Egyptian patients compared with 25 controls using quantitative reverse-transcription polymerase chain reaction assay. The sensitivity and specificity were evaluated using receiver operating characteristic (ROC) curve. The correlations between their levels and the clinicopathological features were assessed. Fourteen miRNAs showed upregulation and six miRNAs showed downregulation. ROC curve analyses revealed that the explored miRNAs could serve as valuable biomarkers for chronic hepatitis with an area under the curve ranged from 0.708 (95% confidence interval [95% CI], 0.587 to 0.829; P = 0.004) for miR-199 up to 0.974 (95% CI, 0.943 to 1.00; P < 0.001) for miR-23b. The expression level of miR-21 demonstrated significant correlation with age, liver enzymes, ALT/AST, and α-fetoprotein level. AST level was directly correlated with miR-122, while an inversely correlated with miR-23b. Fibrosis and steatosis stages possessed positive correlation with miR-199 expression and negative correlation with miR-27a and miR-93. In conclusion, miR-23b and miR-106 might be a useful biomarker for chronic hepatitis C (CHC). MiR-27a, miR-93, and miR-199 might have a potential role in the progression of liver diseases. Unravel the role of these miRNAs in CHC patients might lead to precise prognosis and management.

Circulating microRNAs panel as a diagnostic tool for discrimination of HCV-associated hepatocellular carcinoma.

Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve the overall survival of HCC patients. However, current diagnostic markers are compromised and limited by their low sensitivity and specificity. In this work, circulating microRNAs (miRs) were utilized as a diagnostic tool to test their efficiency to segregate HCC and hepatitis C virus (HCV)-infected patients from healthy subjects. Nine HCC-related miRs (miR-21, miR-30c, miR-93, miR-122, miR-125b, miR-126, miR-130a, miR-193b and miR-222) were analyzed by Real-Time PCR in 86 serum samples; 34 HCC and 52 HCV patients in addition to 25 healthy subjects. The sensitivity and specificity of these miRs were assessed. Our results demonstrated that the median serum level of seven miRs was significantly reduced (P ranges from <0.01 to<0.001) in HCC patients whereas nine miRs were reduced (P<0.001) in HCV compared to healthy controls. Receiver operating characteristic (ROC) curve analyses had shown high diagnostic accuracy (AUC=1.0) when seven and nine combined miRs were considered in HCC and HCV groups, respectively compared to their counterparts. However, a combination of differentially expressed miRs did not improve the discriminatory power (AUC=0.742) when HCC compared to non-HCC groups. miR-122 showed the highest sensitivity and specificity to stratify HCC and HCV versus normal individuals and HCC versus HCV patients. We conclude that differentially expressed miRs in the serum of HCV and HCC patients can be utilized as surrogate and non-invasive biomarker for segregation of HCV and HCC patients from healthy subjects.