An approach for an enhanced anticancer activity of ferulic acid-loaded polymeric micelles via MicroRNA-221 mediated activation of TP53INP1 in caco-2 cell line.

Ferulic acid (FA) has powerful antioxidant and antitumor activities, but it has low bioavailability owing to its poor water solubility. Our aim is to formulate polymeric mixed micelles loaded with FA to overcome its poor solubility and investigate its potential anticancer activity via miRNA-221/TP53INP1 axis-mediated autophagy in colon cancer. A D-optimal design with three factors was used for the optimization of polymeric mixed micelles by studying the effects of each of total Pluronics mixture (mg), Pluronic P123 percentage (%w/w), and drug amount (mg) on both entrapment efficiency (EE%) and particle size. The anticancer activity of FA and Tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles formula (O2) was assessed by MTT and flow cytometry. O2 showed an EE% of 99.89%, a particle size of 13.86 nm, and a zeta potential of - 6.02 mv. In-vitro drug release studies showed a notable increase in the release rate of FA from O2, as compared to the free FA. The (IC50) values for FA from O2 and free FA were calculated against different cell lines showing a prominent IC50 against Caco-2 (17.1 µg/ml, 191 µg/ml respectively). Flow cytometry showed that FA caused cell cycle arrest at the G2/M phase in Caco-2. RT-PCR showed that O2 significantly increased the mRNA expression level of Bax and CASP-3 (4.72 ± 0.17, 3.67 ± 0.14), respectively when compared to free FA (2.59 ± 0.13, 2.14 ± 0.15), while miRNA 221 levels were decreased by the treatment with O2 (0.58 ± 0.02) when compared to free FA treatment (0.79 ± 0.03). The gene expression of TP53INP1 was increased by the treatment with O2 compared to FA at P < 0.0001. FA-loaded TPGS mixed micelles showed promising results for enhancing the anticancer effect of FA against colorectal cancer, probably due to its enhanced solubility. Thus, FA-loaded TPGS mixed micelles could be a potential therapeutic agent for colorectal cancer by targeting miRNA-221/TP53INP1 axis-mediated autophagy.

Nanotechnology in leukemia: diagnosis, efficient-targeted drug delivery, and clinical trials.

Leukemia is a group of malignant disorders which affect the blood and blood-forming tissues in the bone marrow, lymphatic system, and spleen. Many types of leukemia exist; thus, their diagnosis and treatment are somewhat complicated. The use of conventional strategies for treatment such as chemotherapy and radiotherapy may develop many side effects and toxicity. Hence, modern research is concerned with the development of specific nano-formulations for targeted delivery of anti-leukemic drugs avoiding toxic effects on normal cells. Nanostructures can be applied not only in treatment but also in diagnosis. In this article, types of leukemia, its causes, diagnosis as well as conventional treatment of leukemia shall be reviewed. Then, the use of nanoparticles in diagnosis of leukemia and synthesis of nanocarriers for efficient delivery of anti-leukemia drugs being investigated in in vivo and clinical studies. Therefore, it may contribute to the discovery of novel and emerging nanoparticles for targeted treatment of leukemia with less side effects and toxicities.

Association of XIST/miRNA155/Gab2/TAK1 cascade with the pathogenesis of anti-phospholipid syndrome and its effect on cell adhesion molecules and inflammatory mediators.

Anti-phospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and miscarriage events. Still, the molecular mechanisms underlying APS, which predisposes to a wide spectrum of complications, are being explored. Seventy patients with primary and secondary APS were recruited, in addition to 35 healthy subjects. Among APS groups, the gene expression levels of XIST, Gab2, and TAK1 were higher along with declined miRNA155 level compared with controls. Moreover, the sera levels of ICAM-1, VCAM-1, IL-1ꞵ, and TNF-α were highly elevated among APS groups either primary or secondary compared with controls. The lncRNA XIST was directly correlated with Gab2, TAK1, VCAM-1, ICAM-1, IL-1ꞵ, and TNF-α. The miRNA155 was inversely correlated with XIST, Gab2, and TAK1. Moreover, ROC curve analyses subscribed the predictive power of the lncRNA XIST and miRNA155, to differentiate between primary and secondary APS from control subjects. The lncRNA XIST and miRNA155 are the upstream regulators of the Gab2/TAK1 axis among APS patients via influencing the levels of VCAM-1, ICAM-1, IL1ꞵ, and TNF-α which propagates further inflammatory and immunological streams. Interestingly, the study addressed that XIST and miRNA155 may be responsible for the thrombotic and miscarriage events associated with APS and provides new noninvasive molecular biomarkers for diagnosing the disease and tracking its progression.

A novel lupene derivative from Thymus capitatus possesses an apoptosis-inducing effect via Let-7 miRNA/Cyclin D1/VEGF cascade in the A549 cell line.

Non-small-cell lung carcinoma (NSCLC) is a type of epithelial lung cancer accounting for about 85% of all lung cancers. In our research, a novel lupene derivative namely acetoxy-lup-5(6), 20(29)-diene (ALUP), as well as two known triterpenes; lupeol (LUP) and betulinic acid (BA) were isolated through the chromatographic purification of the 95% ethanolic extract of Thymus capitatus. Identification of the compounds was carried out by physicochemical properties as well as spectral 1D and 2D NMR analysis. The anti-cancer activity of the three triterpenes was assessed on non-small cell lung cancer cell line; A549 using MTT assay and cell cycle analysis using annexin V/propidium iodide. The molecular mechanism underlying anti-apoptotic effects was determined by analyzing Let-7 miRNA and miRNA-21 expression, the mRNA gene expression level of Bax, CASP-8, CD95, Bcl2, KRAS, VEGF, Cyclin D1 using qRT-PCR. Our results revealed that the three isolated compounds ALUP, LUP, and BA caused cell cycle arrest at the G2/M phase with an increase in the apoptosis which may be attributed to their significant effect on raising Bax, CASP-8, and CD95 and reducing the mRNA expression levels of Bcl-2, KRAS, VEGF, and Cyclin D1 compared to control cells. RT-PCR results showed that the ALUP, LUP, and BA significantly downregulated miRNA-21 expression. Meanwhile, the three compounds caused significant overexpression of Let-7 miRNA. This is the first report on the anti-cancer activity of acetoxy-lup-5(6), 20(29)-diene (ALUP) in reducing the proliferation and differentiation of the A549 cell line through inducing apoptosis. Finally, by targeting the Let-7 miRNA/Cyclin D1/VEGF cascade, acetoxy-lup-5(6), 20(29)-diene could be a potential therapeutic agent for lung cancer.

Acovenoside A as a novel therapeutic approach to boost taxol and carboplatin apoptotic and antiproliferative activities in NSCLC: Interplay of miR-630/miR-181a and apoptosis genes.

The aim of the present study is to explore the potential anticancer effect of the cardenolide; acovenoside A against non-small cell lung cancer (NSCLC), understand its molecular mechanism in inducing apoptosis and show the effect of its combination with carboplatin and taxol. MTT assay showed that the combination of acovenoside A with taxol and carboplatin caused 78.9% cytotoxicity reflecting the synergistic effect. The triple combination showed the best growth inhibition efficiency where the number of cells at the G2/M phase was decreased and boosted up apoptotic and necrotic activity. The combination also showed the most remarkable increase in gene expression of Bax and p53 and the least level of Bcl2. The gene expression of miRNA181a and miRNA630 was significantly upregulated in cell lines treated with the combination. The present study has proven that the underlying mechanism of acovenoside A is partially attributed to the upregulation of miR-630 and miR-181a gene expressions which in turn targets the intrinsic apoptosis genes as p53, Bax and Bcl2 as well as caspase 3. The present study is the first to address the valuable effect of using acovenoside A together with carboplatin and taxol in the treatment of NSCLC via exerting apoptotic, antiproliferative, and cytotoxic effects..

Circular SERPINA3 and its target microRNA-944 as potential biomarkers in hepatitis C virus-induced hepatocellular carcinoma in Egyptian population.

Background: The most prevalent cancer in Egypt is hepatocellular carcinoma (HCC) mainly due to the infection with the hepatitis C virus. So it is critical to find sensitive biomarkers for early diagnosis of HCC and avoid post-operation tumor recurrence. Therefore, this research was designed to demonstrate the circSERPINA3 role in the regulation of microRNA-944 gene expression in HCV-related HCC cases and compare these results with circSERPINA3 and microRNA-944 gene expression levels in HCV-infected patients. Methodology: Study participants were divided into three groups: healthy controls, HCV- infected, and HCV-induced HCC patients. The gene expression levels of circSERPINA3 and microRNA-944 were evaluated using Real-Time qPCR. Then the immunoblotting procedure was applied to measure the serum levels of MDM2 and E-cadherin besides, the serum concentration levels of glypican-3 and alpha-fetoprotein were measured by sandwich ELISA. Results: The gene expression level of circSERPINA3 was significantly upregulated in both HCV-infected and HCC patients causing suppression of the antitumor effect of miR-944 and showing a lower 1-year survival rate than the participants who had low circSERPINA3 gene expression levels. Subsequently, the miR-944 downstream protein, MDM2 was remarkably upregulated, exaggerating the metastasis and oxidative stress in HCC cases. Additionally, the results confirmed the downregulation of microRNA-944 improved the progression of viral hepatitis C cases to hepatocarcinogenesis through the significantly increased serum level of the metastatic marker, E-cadherin. Although alpha-fetoprotein is a common diagnostic marker used in the diagnosis of HCC, our results showed that glypican-3 had greater sensitivity and specificity and positively correlated to the IGF-1 signaling pathway of HCC cases. Moreover, the gene expression levels of circSERPINA3 and E-cadherin in both the HCV and HCV-induced HCC were significantly positively correlated. Conclusion: circSERPINA3 and miR-944 were sensitive molecular markers for early diagnosis of HCC and could be prospective treatment targets for HCV-infected patients to avoid tumor recurrence in HCC cases.

Development of Semisynthetic Apoptosis-Inducing Agents Based on Natural Phenolic Acids Scaffold: Design, Synthesis and In-Vitro Biological Evaluation.

A crucial target in drug research is magnifying efficacy and decreasing toxicity. Therefore, using natural active constituents as precursors will enhance both safety and biological activities. Despite having many pharmacological activities, caffeic and ferulic acids showed limited clinical usage due to their poor bioavailability and fast elimination. Therefore, semisynthetic compounds from these two acids were prepared and screened as anticancer agents. In this study, CA and FA showed very potent anticancer activity against Caco-2 cells. Consequently, eighteen derivatives were tested against the same cell line. Four potent candidates were selected for determination of the selectivity index, where compound 10 revealed a high safety margin. Compound 10 represented a new scaffold and showed significant cytotoxic activity against Caco-2. Cell-cycle analysis and evaluation of apoptosis showed that derivatives 10, 7, 11, 15 and 14 showed the highest proportion of cells in a late apoptotic stage.

Artemisia spp.: An Update on Its Chemical Composition, Pharmacological and Toxicological Profiles.

Artemisia plants are traditional and ethnopharmacologically used to treat several diseases and in addition in food, spices, and beverages. The genus is widely distributed in all continents except the Antarctica, and traditional medicine has been used as antimalarial, antioxidant, anticancer, antinociceptive, anti-inflammatory, and antiviral agents. This review is aimed at systematizing scientific data on the geographical distribution, chemical composition, and pharmacological and toxicological profiles of the Artemisia genus. Data from the literature on Artemisia plants were taken using electronic databases such as PubMed/MEDLINE, Scopus, and Web of Science. Selected papers for this updated study included data about phytochemicals, preclinical pharmacological experimental studies with molecular mechanisms included, clinical studies, and toxicological and safety data. In addition, ancient texts and books were consulted. The essential oils and phytochemicals of the Artemisia genus have reported important biological activities, among them the artemisinin, a sesquiterpene lactone, with antimalarial activity. Artemisia absinthium L. is one of the most famous Artemisia spp. due to its use in the production of the absinthe drink which is restricted in most countries because of neurotoxicity. The analyzed studies confirmed that Artemisia plants have many traditional and pharmacological applications. However, scientific data are limited to clinical and toxicological research. Therefore, further research is needed on these aspects to understand the full therapeutic potential and molecular pharmacological mechanisms of this medicinal species.

Coriander (Coriandrum sativum L.) essential oil and oil-loaded nano-formulations as an anti-aging potentiality via TGFß/SMAD pathway.

Aging has become a concern for many people, especially women. Given that high-quality anti-aging products are of high cost; it has imperative to search for other economical sources. Essential oils are frequently used in cosmetics products due to a wide range of biological activities as well as their pleasant odor. The current study aimed to investigate the biochemical effect of the cosmetic potential of selected Apiaceous essential oils, traditionally used for skincare, by evaluating their anti-wrinkle activity. It is worth noting that, coriander essential oil showed the highest collagenase, elastase, tyrosinase, and hyaluronidase inhibitory activities compared to other Apiaceous oils (fennel, anise, and cumin). GC-MS proved that coriander essential oil showed a very high level of oxygenated monoterpenes, with linalool (81.29%) as the most abundant constituent. Intriguingly, coriander oil cream and Coriander Essential Oil-loaded Lipid Nanoparticles (CEOLNs) formulations attenuated in vivo UV-induced skin photoaging that was manifested by significantly decreased MDA, COX-2, PGE-2, MMP-1, JNK, and AP-1 levels. Moreover, these pharmaceutical dosage forms significantly increased skin collagen content compared to UV-injured group. Also, coriander essential oil significantly increased TGFß, TGFßII, and SMAD3 protein expression levels compared to UV-injured group. In conclusion, the pharmaceutical dosage forms of coriander oil possess anti-wrinkle activities that could have an auspicious role in amending extrinsic aging.

Anti-Oxidant and Anti-Inflammatory Effects of Lipopolysaccharide from Rhodobacter sphaeroides against Ethanol-Induced Liver and Kidney Toxicity in Experimental Rats.

This study aimed to investigate the protective effects of lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) against ethanol-induced hepatotoxicity and nephrotoxicity in experimental rats. The study involved an intact control group, LPS-RS group, two groups were given ethanol (3 and 5 g/kg/day) for 28 days, and two other groups (LPS-RS + 3 g/kg ethanol) and (LPS-RS + 5 g/kg ethanol) received a daily dose of LPS-RS (800 µg/kg) before ethanol. Ethanol significantly increased the expression of nuclear factor kappa B (NF-κB) and levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the liver tissue and decreased anti-oxidant enzymes. Hepcidin expression was downregulated in the liver, with increased serum levels of ferritin and iron. Prior-administration of LPS-RS alleviated the increase in oxidative stress and inflammatory markers, and preserved iron homeostasis markers. In the kidney, administration of ethanol caused significant increase in the expression of NF-κB and the levels of TNF-α and kidney injury markers; whereas LPS-RS + ethanol groups had significantly lower levels of those parameters. In conclusion; this study reports anti-oxidant, anti-inflammatory and iron homeostasis regulatory effects of the toll-like receptor 4 (TLR4) antagonist LPS-RS against ethanol induced toxicity in both the liver and the kidney of experimental rats.

Gallic acid potentiates the apoptotic effect of paclitaxel and carboplatin via overexpression of Bax and P53 on the MCF-7 human breast cancer cell line.

Despite advances in treatment, breast cancer remains the widest spread disease among females with a high mortality rate. We investigated the potential effects of gallic acid (GA) as supportive therapy in the management of breast cancer. Anti-cancer activity with GA alone or in combination with paclitaxel and/or carboplatin was assessed by MTT assay and flow cytometry using annexin V/propidium iodide. The mechanism underlying the antiproliferative effects was investigated by measuring the expression of the pro-apoptotic marker (Bax), CASP-3, anti-apoptotic (Bcl-2), and, tumor suppressor (p53) by real-time polymerase chain reaction (RT-PCR) and western blot analysis. Cell cycle analysis was performed for the MCF-7 breast cancer cell line. GA, paclitaxel, and carboplatin alone or in combination arrested cell cycle progression at the G2/M phase and induced Pre-G1 apoptosis. RT-PCR showed that the triplet combination significantly raised P53, Bax, and CASP-3 mRNA expression (20.1 ± 1.41, 16.6 ± 0.43, and 20.04 ± 1.61, respectively) in MCF-7 cells when compared to single or combined treatment (p < .0001) while anti-apoptotic Bcl-2 mRNA levels were decreased in all treated groups compared to untreated cells. Western blot data of tested apoptotic factors were consistent with RT-PCR results. For the first time, we show that a minimum non-toxic concentration of GA increased the efficacy of paclitaxel- and carboplatin-induced MCF-7 apoptotic cell death.

Effect of Gallic acid in potentiating chemotherapeutic effect of Paclitaxel in HeLa cervical cancer cells.

BACKGROUND: Cervical cancer is the fourth most common cancer affecting women worldwide. Paclitaxel/Carboplatin is one of the most commonly prescribed regimens in cervical cancer treatment. Although chemotherapeutic drugs are very effective, severe side effects and development of drug resistance limits the use of these drugs. The use of natural products with anticancer activity may help to partially overcome these issues. METHODS: In the present study, we investigated the ability of Gallic acid, to potentiate the anti-cancer effects of Paclitaxel, Carboplatin and Paclitaxel/Carboplatin combination in human HeLa cells by performing MTT assay, cell cycle analysis and RT-PCR assay and Western blotting for some apoptotic markers. RESULTS: Our results revealed that the highest cytotoxic effect, the highest induction of apoptosis and significant elevation in P53 and Caspase 3 levels was seen in Paclitaxel/Gallic acid combination. CONCLUSION: These results indicate that Gallic acid potentiates Paclitaxel effect and that Paclitaxel/Gallic acid combination could represent a promising alternative with lower side effects-for Paclitaxel/Carboplatin combination in treatment of cervical cancer treatment.

IL-6 and NFE2L2: A putative role for the hepatoprotective effect of N. Sativa, P. Ginseng and C. Sempervirens in AFB-1 induced hepatocellular carcinoma in rats.

In this study, we investigated possible hepato-protective effects of N. Sativa, P. Ginseng, and C. Sempervirens in Aflatoxin B1 (AFB-1) induced hepatocellular carcinoma rat model. Fifty-four male albino rats were randomly assigned to experimental groups. Alcoholic extracts of aforementioned herbs were administered orally for 28 days at different doses. IL-6, hs-CRP, MDA, SOD and NFE2L2 were determined using ELISA. Histopathological changes in treated groups were examined. Herbal treatment significantly reduced IL-6, hs-CRP, and MDA (P < 0.001) whereas it significantly increased SOD (p < 0.001). C. Sempervirens 600 and N. Sativa 1000 increased NFE2L2 level compared to P. Ginseng 500 group (P value<0.01). Histopathological evaluation of treated groups showed different grades of healing of the liver. This study confirms a beneficial hepatoprotective effect for aforementioned herbal extracts orally administered in rat model of AFB1 induced HCC. This effect is putatively mediated via modulation of inflammatory cytokines as well as amelioration of oxidative stress.

Resistin mediates tomato and broccoli extract effects on glucose homeostasis in high fat diet-induced obesity in rats.

BACKGROUND: Resistin is an adipocyte hormone that regulates glucose metabolism. Elevated levels of resistin may cause insulin resistance. This may link obesity, and increased fat mass to type II diabetes and insulin resistance. We hypothesized that treatment with tomato and broccoli extracts regulates glucose homeostasis via modulation of resistin levels in high fat diet-induced obesity rats (HFD). METHODS: Forty-eight male albino rats were divided into 8 groups as follows: control, HFD, stop fat diet (SD), Tomato 200 mg/kg (T200), Tomato 400 mg/kg (T400), Broccoli 200 mg/kg (B200), Broccoli 400 mg/kg (B400), and Chromax (CX). Treatment continued for 1 month. Serum levels of resistin, leptin, adiponectin, glucose and insulin were measured using ELISA and spectrophotometry. RESULTS: Serum levels of resistin were significantly reduced in the T 200, T 400, B 200, B 400 and CX groups to: 4.13 ± 0.22 ng/ml, 1.51 ± 0.04 ng/ml, 4.13 ± 0.22 ng/ml, 2.32 ± 0.15 ng/ml and 1.37 ± 0.03 ng/ml, respectively, compared to HFD group and SD group (P value < 0.0001). Non-significant differences were found between T 400, B 400 and CX groups. Serum levels of leptin were significantly reduced in the T 400 (22.7 ± 0.84 pg/ml) group compared to the B 400 (41 ± 2.45 Pg/ml) and CX groups (45.7 ± 2.91 Pg/ml), P value < 0.001. Serum levels of adiponectin were significantly increased in the T 400 group (131 ± 3.84 pg/ml) compared to the CX group (112 ± 4.77 pg/ml), P value < 0.01. CONCLUSIONS: Our results demonstrate that tomato and broccoli extract treatment regulates glucose homeostasis via reduction of serum resistin and may be a useful non-pharmacological therapy for obesity.