The Expression of Circulating miR-497 and Metadherin in Hepatocellular Carcinoma: Relation to the Tumor Characteristics and Patients' Survival.

Objectives: This study aimed to evaluate the prognostic significance and relationship of miR-497 and metadherin to hepatocellular carcinoma (HCC) tumor characteristics and patients' survival. Methods: This study enrolled 120 (60 HCC patients and 60 healthy) subjects. Serum miR-497 and metadherin mRNA relative expression were analyzed by real-time quantitative reverse transcription polymerase chain reaction. The overall survival (OS) of HCC patients was assessed using the Kaplan-Meier curve and log-rank test. Results: Serum miR-497 showed statistically significant downregulation in HCC patients compared to controls (p < 0.001). Serum metadherin mRNA relative expression was significantly upregulated in HCC patients compared to controls (p < 0.001). Both serum miR-497 and metadherin mRNA expression were significantly associated with the number of tumor foci (p = 0.028 and 0.001, respectively), tumor size (p = 0.022 and <0.001, respectively), nodal metastasis (p = 0.003 and 0.003, respectively), distant metastasis (p = 0.003 and 0.003, respectively), vascular invasion (p = 0.040 and <0.001, respectively), and BCLC staging (p = 0.043 and 0.004, respectively). The overall survival was lower in patients with low miR-497 expression (p = 0.046) and in patients with high metadherin expression (p < 0.001). Conclusions: The expression levels of miR-497 showed downregulation in HCC patients, but metadherin expression showed upregulation. Both markers were inversely related and closely correlated with tumor characteristics and patients' survival.

The Prognostic Significance of MACC1 Expression in Breast Cancer and Its Relationship to Immune Cells in the Tumor Microenvironment and Patient Survival.

Breast cancer (BC) is one of the most prevalent malignancies among females worldwide. Globally, distant metastases were reported to be responsible for a large proportion of breast cancer-related deaths. The metastasis-associated colon cancer-1 (MACC1) gene was reported as a reliable biomarker for early detection of metastasis and prediction of prognosis of breast cancer. This study investigated the prognostic significance of MACC1 in breast cancer in relation to the clinicopathologic characteristics and patients' survival. Furthermore, the possible correlation between MACC1 expression and the different immune cells in the tumor microenvironment was explored. MACC1 mRNA was identified using quantitative reverse transcription polymerase chain reaction in 120 breast cancer specimens and adjacent non-cancerous tissues. MACC1 mRNA expression was significantly higher in the cancerous relative to the non-cancerous tissues (p < 0.001). High MACC1 expression was significantly associated with poor prognostic parameters, such as larger tumor size, grade III tumors, positive nodal metastasis, lymphovascular invasion, stage III tumors, and elevated Ki-67 expression. Higher MACC1 mRNA levels were positively correlated with CD163+ tumor-associated macrophages (r = 0.614, p < 0.001), and were negatively correlated with CD56+ natural killer cells (r = -0.398, p < 0.001) and CD8+ cytotoxic T lymphocytes (r = -0.323, p < 0.001). MACC1 expression was associated with poor patient overall survival (OS) and progression-free survival (PFS) (p < 0.001). Multivariate analysis suggested that MACC1 expression and the presence of lymphovascular invasion could be independent prognostic indicators for breast cancer (p = 0.015 and 0.042, respectively). In conclusion, MACC1 is highly expressed in cancerous tissues and is significantly related to poor prognostic factors, overall survival, and progression-free survival. MACC1 may influence infiltration of the immune cells in the tumor microenvironment, enhance immune escape of tumor cells, and may serve as a reliable independent prognostic factor for breast cancer.

Expression of long non-coding RNA CCHE1 in colorectal carcinoma: correlations with clinicopathological features and ERK/COX-2 pathway.

Colorectal cancer (CRC) is among the leading causes of cancer-related mortality worldwide. Compelling evidence suggests that long non-coding RNA (lncRNAs) can control carcinogenesis by regulating various aspects of cell biology. However, limited number of CRC-related lncRNAs has been well characterized. This study was undertaken to investigate the expression pattern of the novel lncRNA-CCHE1 in CRC patients and to examine its correlation with clinicopathological features, ERK/COX-2 pathway and some cell proliferation markers in order to gain biological insights on its role in CRC pathogenesis. Colon cancer specimens with their adjacent non-cancerous tissues were taken from 60 patients with primary CRC. LncRNA-CCHE1 relative expression was assessed using quantitative real-time RT-PCR. P-ERK ½ and cyclin D1 levels were estimated by ELISA. COX-2 and proliferating cell nuclear antigen (PCNA) expression were assessed immunohistochemically. lncRNA-CCHE1 expression was upregulated in CRC tissues compared to adjacent non-cancerous tissues, and was significantly associated with larger tumor size, less differentiated histology, advanced dukes' stage, positive lymph node involvement and vascular invasion. It also showed a significant positive correlation with the expression of p-ERK1/2, COX-2 as well as cyclin D1and PCNA (as markers for cell proliferation). These findings signify that lncRNA-CCHE1 is a key oncogene possibly involved in CRC development and progression by modulating ERK/COX-2 pathway and cell proliferation activity. Our study also provides a rationale for potential use of lncRNA-CCHE1 as a novel prognostic marker, and opens the door for the development of lncRNA-CCHE1-directed therapeutic approaches for CRC patients.

Hesperidin modulates dextran sulfate sodium-induced ulcerative colitis in rats: Targeting sphingosine kinase-1- sphingosine 1 phosphate signaling pathway, mitochondrial biogenesis, inflammation, and apoptosis.

Ulcerative colitis (UC) is a chronic gastrointestinal disorder interfering with life quality. A total of 60 male Wistar rats were divided into four equal groups: Control (group I), hesperidin only (group II), UC untreated (group III), and UC treated with hesperidin (group IV). Hesperidin had modulatory effects on UC pathogenesis, which might be through alleviating colonic sphingosine phosphate phosphatase 2 messenger RNA expression and sphingosine kinase-1 levels, thus suppressing the subsequent downstream inflammatory and apoptotic cascades represented by decreased macrophage inflammatory protein-1α and enhancement of B-cell lymphoma 2 immunohistochemistry expression. Also, it improved mitochondrial biogenesis by increasing the peroxisome proliferator-activated receptor-gamma-coactivator 1-α level. It successfully restored redox potential as evidenced by marked alleviations of the nitric oxide and peroxynitrite levels, increasing total antioxidant capacity, and activating the superoxide dismutase enzyme. Also, hesperidin alleviated the UC disease activity index and improved the histopathological picture. These findings may offer a new therapeutic strategy for UC treatment.

Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms.

BACKGROUND: Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. AIM: This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). METHODS: Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC+5-FU, SEC+apigenin, SEC+ 5-FU+apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. RESULTS: 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. IN CONCLUSION: The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice.

Green Synthesized Zinc Oxide Nanoparticles Using Moringa olifera Ethanolic Extract Lessens Acrylamide-Induced Testicular Damage, Apoptosis, and Steroidogenesis-Related Gene Dysregulation in Adult Rats.

This study assessed the possible protective role of green synthesized zinc oxide nanoparticles using Moringa olifera leaf extract (MO-ZNPs) in acrylamide (ACR)-induced reproductive dysfunctions in male rats. ACR (20 mg/kg b.wt/day) and/or MO-ZNPs (10 mg/kg b.wt/day) were given orally by gastric gavage for 60 days. Then, sperm parameters; testicular enzymes; oxidative stress markers; reproductive hormones including testosterone, luteinizing hormone (LH)-estradiol, and follicle-stimulating hormone (FSH) concentration; testis histology; steroidogenesis-related gene expression; and apoptotic markers were examined. The findings revealed that MO-ZNPs significantly ameliorated the ACR-induced decline in the gonadosomatic index and altered the pituitary-gonadal axis, reflected by decreased serum testosterone and FSH with increased estradiol and LH, and sperm analysis disruption. Furthermore, a notable restoration of the tissue content of antioxidants (catalase and reduced glutathione) but depletion of malondialdehyde was evident in MO-ZNPs+ACR-treated rats compared to ACR-exposed ones. In addition, MO-ZNPs oral dosing markedly rescued the histopathological changes and apoptotic caspase-3 reactions in the testis resulting from ACR exposure. Furthermore, in MO-ZNPs+ACR-treated rats, ACR-induced downregulation of testicular steroidogenesis genes and proliferating cell nuclear antigen (PCNA) immune-expression were reversed. Conclusively, MO-ZNPs protected male rats from ACR-induced reproductive toxicity by suppressing oxidative injury and apoptosis while boosting steroidogenesis and sex hormones.

Stabilization of glutathione redox dynamics and CYP2E1 by green synthesized Moringa oleifera-mediated zinc oxide nanoparticles against acrylamide induced hepatotoxicity in rat model: Morphometric and molecular perspectives.

The terrible reality is that acrylamide (AA) is a common food contaminant found in a wide variety of commonly consumed foods. This research involves the advancement of a more dependable technique for the bio-fabrication of zinc oxide nanoparticles (ZNPs) through the green method using Moringa Oleifera extract (MO-ZNPs) as an efficient chelating agent for acrylamide (AA). The effects of AA on glutathione redox dynamics, liver function, lipid profile, and zinc residues in Sprague Dawley rats are investigated. Finally, the microarchitecture and immunohistochemical staining of Caspase-3 and CYP2E1 were determined in the liver tissue of rats. Four separate groups, including control, MO-ZNPs (10 mg/kg b. wt), AA (20 mg/kg b. wt), and AA + MO-ZNPs for 60 days. The results revealed a suppressed activity of glutathione redox enzymes (GSH, GPX,and GSR) on both molecular and biochemical levels. Also, AA caused elevated liver enzymes, hepatosomatic index, and immunohistochemical staining of caspase-3 and CYP2E1 expression. MO-ZNPs co-treatment, on the other hand, stabilized glutathione-related enzyme gene expression, normalized hepatocellular enzyme levels, and restored hepatic tissue microarchitectures. It could be assumed that MO-ZNPs is a promising hepatoprotective molecule for alleviating AA-induced hepatotoxicity. We witnessed changes in glutathione redox dynamics to be restorative. Glutathione and cytochrome P450 2E1 play crucial roles in AA detoxification, so maintaining a healthy glutathione redox cycle is necessary for disposing of AA toxicity.

Curcumin-loaded chitosan nanoparticles alleviate fenpropathrin-induced hepatotoxicity by regulating lipogenesis and pyroptosis in rats.

In this study, the probable alleviative role of curcumin (CMN) (50 mg/kg b.wt) or curcumin-loaded chitosan nanoparticle (CLC-NP) (50 mg/kg b.wt) was assessed against the hepatotoxic effect of a widely used pyrethroid insecticide, fenpropathrin (FEN) (15 mg/kg b.wt) in rats in a 60-day experiment. The results revealed that CMN and CLC-NP significantly suppressed the FEN-induced increment in serum hepatic enzyme activities (ALT, AST, and ALP) and hyperbilirubinemia. Moreover, FEN-associated dyslipidemia, hepatic oxidative stress, and altered hepatic histology were significantly rescued by CMN and CLC-NP. Furthermore, the increased TNF-α and Caspase-3 immunoexpression in hepatic tissues of FEN-exposed rats was significantly reduced in CMN and CLC-NP-treated ones. FEN exposure significantly upregulated the pyroptosis-related genes, including GSDMD, Casp-1, Casp-3, Casp-8, IL-18, TNF-α, IL-1ß, and NF-κB and altered the expression of lipogenesis-related genes including SREBP-1c, PPAR-α, MCP1, and FAS in the hepatic tissues. Nevertheless, the earlier disturbances in gene expression were corrected in CMN and CLC-NP-treated groups. Of note, compared to CMN, CLC-NP was more effective at inhibiting oxidative damage and controlling lipogenesis and pyroptosis in the hepatic tissues of FEN-exposed rats. Conclusively, the current study findings proved the superior and useful role of CLC-NP in combating pollutants associated with hepatic dysfunction.

Scrutinizing pathways of nicotine effect on renal Alpha-7 nicotinic acetylcholine receptor and Mitogen-activated protein kinase (MAPK) expression in Ehrlich ascites carcinoma-bearing mice: Role of Chlorella vulgaris.

Nicotine is one of several physiologically stable and active chemicals found in tobacco. The mechanism through which nicotine causes kidney damage is still obscure. As a result, the goal of this research was to investigate how oral nicotine intake can lead to kidney damage. Naturaly occurring superfood green algae are immense supplements help us using extra chemicals during cancer prevalence if the patient is exposed to nicotine. Hence, the mitigating role of Chlorella vulgaris extract (CVE) against nicotine-nephrotoxic impact in Ehrlich ascites carcinoma (EAC)-bearing mice was studied. For this purpose, four groups of Swiss female mice were assigned, nicotine group (NIC) (100 µg/ml/kg), CVE group (100 mg/kg), CVE + Nicotine, and a control group. Renal dysfunction was evaluated by estimating serum biomarkers ofrenal damage. The expression pattern of Nf-KB, MAPK, P53, and α7-nAchR, lipid peroxidation biomarker, and antioxidant enzyme activities were evaluated in kidney tissue. Also, micro-morphometric examination and apoptosis immunohistochemical reactivity of kidney tissue were applied. The obtained results indicated up-regulation of all estimated genes and oxidative stress. Moreover, a significant (P < 0.05) increment in the apoptotic marker Caspase-3 and declined BCL-2 proteins were recorded. In serum, a significant (P < 0.05) elevation of urea, creatinine, TNF-α, IL-1ß, and Kim-1 were evident. Histological investigation reinforced the aforementioned data, revealing structural changes involving the tubules, glomeruli, and interstitium of mice kidneys. CVE may be a strong contender for protecting renal tissue damage since it reduces renal tissue injury and oxidative stress. Cancer patients who regularly use nicotine through direct smoking or second-hand exposure can benefit from CVE usage as a dietary supplement.

NOD2 expression, DNA damage and oxido-inflammatory status in atopic bronchial asthma: Exploring their nexus to disease severity.

BACKGROUND: Allergic asthma is a chronically relapsing inflammatory airway disease with a complex pathophysiology. AIM: This study was undertaken to investigate the potential contribution of NOD2 signaling, proinflammatory cytokines, chitotriosidase (CHIT1) activity, oxidative stress and DNA damage to atopic asthma pathogenesis, as well as to explore their possible role as surrogate noninvasive biomarkers for monitoring asthma severity. METHODS: Sixty patients with atopic bronchial asthma who were divided according to asthma severity into 40 mild-moderate, 20 severe atopic asthmatics, in addition to thirty age-matched healthy controls were enrolled in this study. NOD2 expression in PBMCs was assessed by quantitative real-time RT-PCR. DNA damage indices were assessed by alkaline comet assay. Serum IgE, IL-17, IL-8 and 3-Nitrotyrosine levels were estimated by ELISA. Serum CHIT1and GST activities, as well as MDA levels, were measured. RESULTS: NOD2 mRNA relative expression levels were significantly decreased in atopic asthmatic cases relative to controls with lower values among severe atopic asthmatics. On the other hand, IL-17 and IL-8 serum levels, CHIT1 activity, DNA damage indices and oxidative stress markers were significantly increased in atopic asthmatic cases relative to controls with higher values among severe atopic asthmatics. The change in these parameters correlated significantly with the degree of decline in lung function. CONCLUSION: The interplay between NOD2 signaling, proinflammatory cytokines, CHIT1 activity, heightened oxidative stress and DNA damage orchestrates allergic airway inflammation and thus contributing to the pathogenesis of atopic asthma. These parameters qualified for measurement as part of new noninvasive biomarker panels for monitoring asthma severity.

High doses of S-methylcysteine cause hypoxia-induced cardiomyocyte apoptosis accompanied by engulfment of mitochondaria by nucleus.

Despite its important role as a medicinal plant, some studies reported a toxic effect for garlic (Allium sativum) when given in higher doses. Herein, we investigated the possible cardiotoxic effects of high doses of S-methylcysteine (SMC), a water soluble organosulfur compound present in garlic. Rats were orally administered SMC at a low dose (50mg), high dose (150mg) and very high dose (300mg)/kg body weight, or saline (control) for 10days. High and very high doses of SMC resulted in a significant increase in serum cardiac injury biomarkers [aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and cardiac troponin T (cTnT)], as well as oxidative stress marker nitric oxide (NO) concentration in heart and a significant decrease in cardiac superoxide dismutase (SOD) activity. Moreover, ultrastructure findings in myocardium of rats treated by high and very high doses showed inter-bundle vacuolation, loss of myofibrils, and centripetal movement of mitochondria towards nucleus. The mitochondria were partially surrounded by nuclear membrane at high dose SMC, and completely engulfed by nucleus at very high dose. This centripetal movement of mitochondria accompanied by cardiomyocytes hypoxia-induced apoptosis as evident by increasing TUNEL positive cells as well as upregulation of apoptotic genes (caspase3 and Bax), hypoxia inducible factor 1 alpha (HIF1α), dynein light chain 1 (DYNLL1) and downregulation of the anti-apoptotic marker, Bcl2. We conclude that high and very high doses of SMC cause hypoxia induced cardiomyocyte apoptosis accompanied by engulfment of mitochondria by nucleus.