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Currently, there is still a lack of effective carriers with minimal side effects to deliver therapeutic miRNA. Thus, it is crucial to optimize novel drug delivery systems. MiR-375 has proven superior therapeutic potency in Hepatocellular carcinoma (HCC). The purpose of this study was to fabricate 2 novel and smart nano-carriers for the transportation efficiency of miR-375 in HCC cells and enhance its anti-tumor effects. We established the miR-375 construct through the pEGP- miR expression vector. Two nano-carriers of solid/liquid lipids and chitosan (CS) were strategically selected, prepared by high-speed homogenization, and optimized by varying nano-formulation factors. Thus, the two best nano-formulations were designated as F1 (0.5% CS) and F2 (1.5% CS) and were evaluated for miR-375 conjugation efficiency by gel electrophoresis and nanodrop assessment. Then, physio-chemical characteristics and stability tests for the miR-375 nano-plexes were all studied. Next, its efficiencies as replacement therapy in HepG2 cells have been assessed by fluorescence microscopy, flow cytometry, and cytotoxicity assay. The obtained data showed that two cationic nanostructured solid/liquid lipid carriers (NSLCs); F1 and F2 typically had the best physio-chemical parameters and long-term stability. Moreover, both F1 and F2 could form nano-plexes with the anionic miR-375 construct at weight ratios 250/1 and 50/1 via electrostatic interactions. In addition, these nano-plexes exhibited physical stability after three months and protected miR-375 from degradation in the presence of 50% fetal bovine serum (FBS). Furthermore, both nano-plexes could simultaneously deliver miR-375 into HepG2 cells and they ensure miR re-expression even in the presence of 50% FBS compared to free miR-375 ( p -value < 0.001). Moreover, both F1 and F2 alone significantly exhibited minimal cytotoxicity in treated cells. In contrast, the nano-plexes significantly inhibited cell growth compared to free miR-375 or doxorubicin (DOX), respectively. More importantly, F2/miR-375 nano-plex exhibited more anti-proliferative activity in treated cells although its IC50 value was 55 times lower than DOX ( p -value < 0.001). Collectively, our findings clearly emphasized the multifunctionality of the two CS-coated NSLCs in terms of their enhanced biocompatibility, biostability, conjugation, and transfection efficiency of therapeutic miR-375. Therefore, the NSLCs/miR-375 nano-plexes could serve as a novel and promising therapeutic strategy for HCC.

Background: miR-210, a key hypoxamiR, regulates hypoxia and inflammation-linked hypoxia. Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is responsible for many pathological disorders, including photosensitivity., Objective: This study aimed to find the correlation between circulating miR-210/HIF-1α levels and photosensitivity in SLE patients and other SLE-associated pathological complications in a single-center case-control study., Methods: The study population comprised 104 SLE Egyptian patients with photosensitivity, 32 SLE patients without photosensitivity, and 32 healthy subjects. SLE activity was assessed for all patients using the SLE Disease Activity Index (SLEDAI). Clinical complications/manifestations and hematological/serological analyses were recorded. HIF-α concentration was investigated by ELISA, and miR-210 expression was analyzed by qRT-PCR., Results: The results revealed that circulating miR-210 was significantly increased in the SLE/photosensitivity group versus the SLE and control groups. The additional occurrence of malar rash, oral ulcers, renal disorders, or hypertension resulted in a higher expression of miR-210. SLEDAI activity status showed no effect on miR-210. Erythrocyte sedimentation rate, white blood cells, hemoglobin, platelets, patient age, and disease duration were positively correlated with circulatory miR-210. HIF-α concentration was significantly induced in the SLE/photosensitivity group versus the SLE and control groups. In SLE/photosensitivity, the presence of renal disorders and hypertension resulted in the highest HIF-α concentrations. A strong positive correlation was recorded between HIF-α concentration and circulatory miR-210 in SLE/photosensitivity patients (r = 0.886)., Conclusion: The dysregulation of circulating miR-210/HIF-1α levels in SLE/ photosensitivity patients is controlled by the presence of additional pathological complications, and results suggest that the hypoxia pathway might interact positively with the pathogenesis and disease progression of SLE., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Chia seed is an oil seed with multiple biological activities. Doxorubicin is effective chemotherapy for liver cancer. Resistance and adverse effects are doxorubicin limitations., Objective: This study aimed to investigate the effect of chia seeds oil (CSO) on the resistance of HepG2 cells to liposomal-doxorubicin (DOX)., Methods: The objective were investigated through measuring cytotoxicity, doxorubicin-metabolizing enzyme Cytochrome P450 3A4 (CYP-3A4), multidrug resistance-associated protein (MRP1), and the expression of multiple tumor suppressor microRNAs., Results: The findings indicated that low concentration of CSO increased HepG2 cells' sensitivity to DOX, as concluded from its higher cytotoxicity. DOX-induced mRNAs of CYP-3A4 and MRP1 and their protein levels. CSO inhibited both in DOX-treated cells. CSO-induced tumor suppressor miRNAs. Doxorubicin inhibited miR-122 and let-7/b/e expression, while it led to overexpression of let- 7a. CSO/DOX upregulated let-7/b/e, miR-34a, and miR-122 (which inhibits MRP1) and downregulated let-7a, which may lead to increased apoptosis., Conclusion: CSO effectively re-sensitized HepG2 cells to liposomal-doxorubicin via inhibiting MRP1 and CYP-3A4, which may increase in vivo doxorubicin bioavailability and decrease its therapeutic dose to diminish its adverse effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: MicroRNAs are fine regulators for gene expression during the post-transcriptional stage in many autoimmune diseases. HypoxamiRs (miR-210 and miR-21) play an important role in hypoxia and in inflammation-associated hypoxia. Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that would potentiate many pathological complications, including hemolytic anemia. This study aimed to investigate the role of hypoxamiRs in SLE/hemolytic anemia patients., Methods: This work was designed to analyze the circulating levels of↱ the miR-210 and miR-21 expressions and hypoxia-inducible factor-1α (HIF-α) in SLE/hemolytic anemia patients. SLE activity was evaluated for all patients by SLE Disease Activity Index (SLEDAI). Clinical manifestations/complications and serological/hematological investigations were reported. HIF-α concentration was assayed by ELISA and expression of miR-21 and miR-210 was analyzed by qRT-PCR., Results: The results indicated that the fold change of the miR-210/miR-21 expressions in plasma was significantly elevated in SLE/hemolytic anemia patients. A strong positive correlation between the miR-210 and miR-21 expression levels was also recorded. Among the associated-disease complications, hypertension, arthritis, oral ulcers, and serositis were associated with a high circulating miR-210 expression, while the occurrence of renal disorders was associated with the increased miR-21 expression. Furthermore, the HIF-α level was remarkably elevated in SLE/hemolytic anemia patients. A high positive correlation was recorded between the HIF-α concentration and miR-210/miR-21 expression levels. The occurrence of oral ulcers, arthritis, and hypertension was associated with the increased HIF-α concentration. On the other hand, SLEDAI and white blood cell count were positively correlated with miR-21/ miR-210. The erythrocyte sedimentation rate was positively correlated with miR-21., Conclusion: The dysregulation of the circulating miR-210/miR-210/HIF-1α levels in SLE/hemolytic anemia patients advocated that the hypoxia pathway might have an essential role in the pathogenesis and complications of these diseases., (© 2022. Huazhong University of Science and Technology.)

Cyclophosphamide (CP) is a mutagen that is used in cancer chemotherapy, due to its genotoxicity and as an immunosuppressive agent . Thalidomide (TH) is another cancer chemotherapeutic drug. In this study, the cytogenotoxicity and hypoxia modulatory activities of two phthalimide analogs of TH have been evaluated with/without CP. Both analogs have increased CP-stimulated chromosomal aberrations than those induced by TH, including gaps, breaks/fragments, deletions, multiple aberrations, and tetraploidy. The analogs have elevated the cytotoxic effect of CP by inhibiting the mitotic activity, in which analog 2 showed higher mitosis inhibition. CP has induced binucleated and polynucleated bone marrow cells (BMCs), while micronuclei (MN) are absent. TH and analogs have elevated the CP-stimulated binucleated BMCs, while only analogs have increased the CP-induced polynucleated BMCs and inhibited the mononucleated BMCs. MN-BMCs were shown together with mononucleated, binucleated, and polynucleated cells in the CP group. Both analogs have elevated mononucleated and polynucleated MN-BMCs, whereas in presence of CP, TH and analogs have enhanced mononucleated and binucleated MN-BMCs. The analogs significantly induce DNA fragmentation in a comet assay, where analog 1 is the strongest inducer. The treatment of mice with CP has resulted in a high hypoxia status as indicated by high pimonidazole adducts and high HIF-1α and HIF-2α concentrations in lymphocytes. Analogs/CP-treated mice showed low pimonidazole adducts. Both analogs have inhibited HIF-1α concentration but not HIF-2α. Taken together, the study findings suggest that both analogs have a higher potential to induce CP-genotoxicity than TH and that both analogs inhibit CP-hypoxia via the HIF-1α-dependent mechanism, in which analog 1 is a more potent anti-hypoxic agent than analog 2. Analog 1 is suggested as an adjacent CP-complementary agent to induce CP-genotoxicity and to inhibit CP-associated hypoxia., Competing Interests: HA is employed by Pharco B International Company for Pharmaceutical Industries, Borg ElArab, Alexandria, Egypt. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gamal-Eldeen, Agwa, Zahran, Raafat, El-Daly, Banjer, Almehmadi, Alharthi, Hawsawi, Althobaiti and Abo-Zeid.)

Sargassum dentifolium , (Turner) C. Agarth, 1820, is an edible brown alga collected from red seashores, Egypt. Oral tongue squamous cell carcinoma (OTSCC) is an aggressive malignancy. Hypoxia leads to chemotherapeutic resistance. This work aimed to explore the anti-hypoxia effect of water-soluble polysaccharide fractions of S. dentifolium (SD1-SD3) in CAL-27 OTSCC cells. Cell cytotoxicity assay (MTT); cell death mode (DNA staining); total hypoxia (pimonidazole), HIF-1α (ELISA and immunocytochemistry), HIF-1β (ELISA), and hsa-miRNA-21-5p and hsa-miRNA-210-3p (qRT-PCR) were investigated. SD1 and SD2 showed a cytotoxic effect due to apoptosis. SD2 and SD3 decreased total cell hypoxia, inhibited miR-210 ( p < 0.001 and p < 0.01), miR-21 ( p < 0.01 and p < 0.05), and HIF-1α ( p < 0.01 and p < 0.05), respectively. However, only SD3 suppressed HIF-1β ( p < 0.05). In conclusion, SD2 showed a potential anti-hypoxia effect through amelioration of HIF-1α regulators, which may help in decreasing hypoxia-induced therapeutic resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer [AAT] declared a shared affiliation with the authors [SE-D] to the handling editor at the time of review., (Copyright © 2022 Gamal-Eldeen, Raafat, Alrehaili, El-Daly, Hawsawi, Banjer, Raafat and Almehmadi.)

Perftoran ® (perfluorodecalin) is an oxygen carrier, and carboplatin is a common chemotherapy drug used worldwide for lung cancer treatment. Hypoxia is one of the factors that induce resistance of lung cancer cells to carboplatin. This study explored the role of Perftoran ® , as an oxygen carrier, in lowering the resistance of lung cancer cells to carboplatin through suppression of hypoxia pathway mediators. The effect of Perftoran ® on the resistance of human lung cancer A549 cells to carboplatin was investigated through the evaluation of cytotoxicity by MTT, cell death mode by dual DNA staining, DNA damage by comet assay, DNA platination (DNA/carboplatin adducts) by atomic absorption spectroscopy, hypoxia degree by pimonidazole, HIF-1α/HIF-2α concentrations by ELISA, expression of miRNAs (hypoxamiRs miR-210, miR-21, and miR-181a) by qRT-PCR, and the content of drug resistance transporter MRP-2 by immunocytochemical staining. Results indicated that compared to carboplatin, Perftoran ® /carboplatin decreased cell resistance to carboplatin by potentiating its cytotoxicity using only 45% of carboplatin IC 50 and inducing apoptosis. Perftoran ® induced DNA platination and DNA damage index in cells compared to carboplatin alone. Moreover, compared to treatment with carboplatin alone, co-treatment of cells with Perftoran ® and carboplatin inhibited cellular pimonidazole hypoxia adducts, diminished HIF-1α/HIF-2α concentrations, suppressed hypoxamiR expression, and decreased MRP-2. In conclusion, Perftoran ® inhibited resistance of lung cancer cells to carboplatin through the inhibition of both hypoxia pathway mediators and the drug resistance transporter MRP-2 and through the induction of DNA/carboplatin adduct formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gamal-Eldeen, Alrehaili, Alharthi and Raafat.)

Indocyanine green (ICG) is a nontoxic registered photosensitizer used as a diagnostic tool and for photodynamic therapy (PDT). Hypoxia is one the main factors affecting PDT efficacy. Perfluorodecalin emulsion (Perftoran ® ) is a known oxygen carrier . This study investigated the effect of Perftoran ® on ICG/PDT efficacy in presence and absence of Perftoran ® via evaluation of phototoxicity by MTT; hypoxia estimation by pimonidazole, HIF-1 α / β by ELISA, and 17 miRNAs (tumor suppressors, oncomiRs, and hypoxamiRs) were analyzed by qPCR. Compared to ICG/PDT, Perftoran ® /ICG/PDT led to higher photocytotoxicity, inhibited pimonidazole hypoxia adducts, inhibited HIF-1 α / β concentrations, induced the expression of tumor-suppressing miRNAs let-7b/d/f/g, and strongly inhibited the pro-hypoxia miRNA let-7i. Additionally, Perftoran ® /ICG/PDT suppressed the expression of the oncomiRs miR-155, miR-30c, and miR-181a and the hypoxamiRs miR-210 and miR-21 compared to ICG/PDT. In conclusion, Perftoran ® induced the phototoxicity of ICG/PDT and inhibited ICG/PDT-hypoxia via suppressing HIF- α / β , miR-210, miR-21, let-7i, miR-15a, miR-30c, and miR-181a and by inducing the expression of let-7d/f and miR-15b., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gamal-Eldeen, Alrehaili, Alharthi and Raafat.)

Background: Interferon-gamma (IFN-γ) is a chief proinflammatory cytokine with a significant role in the immune response against viral infections. Today there is increasing evidence about the association between individual genetic polymorphisms and cytokines in predicting HBV infection susceptibility., Aim: This study aimed to investigate the association between IFN-γ gene polymorphisms and susceptibility to hepatitis B viral infection (HBV), and the impact of these genetic polymorphisms on IFN-γ production. IFN-γ (+874A/T, rs2430561, and +2109A/G, rs1861494) was genotyped by single-stranded polymorphism-polymerase chain reaction (SSP-PCR) in 126 Egyptians with chronic HBV infection and in 100 healthy control subjects. The plasma levels of IFN-γ were measured by Enzyme-linked immunosorbent assay (ELISA)., Results: Compared to the control subjects there was a slight increase in +874TT genotype frequency in HBV patients. However, no statistical significance in IFN-γ (+874A/T and +2109A/G) genotype/allele distribution was demonstrated, indicating the lack of association between these SNPs and susceptibility to HBV infection. In +2109A/G, only AG genotype was observed with a complete abrogation of GG and AA genotypes. Haplotypes between different loci on selected genes showed insignificant changes in their frequency in patients and control subjects. HBV patients had a significantly higher level of IFN-γ (P < 0.001) compared to controls. The maximum significant increase in IFN-γ production was observed in subjects harboring the +874TA genotype., Conclusions: As no association could be characterized between the polymorphism in IFN-γ (+874A/T and +2109A/G) and susceptibility to chronic HBV infection, our data support the concept that IFN-γ gene polymorphisms are not predictors of HBV susceptibility in this segment of the Egyptian population., Competing Interests: The authors report no conflicts of interest in this work.

Background: α-Solanine is a natural toxic glycoalkaloid produced in some species of the Solanaceae family with antiproliferative activity in various cancers., Objective: This study aimed to investigate the effect of α-solanine on the oxidative stress status in human hepatocellular carcinoma HepG2 cells and to evaluate its influence on microRNAs (miRNAs) associated with oxidative stress and NF-κB regulation., Methods: The prooxidant effect of α-solanine was tested by the decay rate of the fluorescent probe, β-phycoerythrin, and by measuring malondialdehyde, reduced Glutathione, catalase, and superoxide dismutase following treatment of HepG2 cells with low doses of α-solanine. Immunocytochemical techniques were used to detect mitochondrial membrane potential (ΔΨm) and NF-κB protein. The gene expression of NF-κB and miRNAs was evaluated by real-time PCR., Results: α-Solanine is a prooxidant that causes a rapid decay in the fluorescence intensity of β-phycoerythrin. It induces oxidative stress-related alterations such as increased lipid peroxidation and reduced antioxidant markers. Oxidative stress induced by α-solanine was mediated by decreased ΔΨm, increased NF-κB expression, upregulation of miRNAs that control oxidative stress by regulating the NF-κB pathway, and downregulation of oncogenic miRNAs that inhibit the NF-κB pathway., Conclusion: α-Solanine-induced oxidative stress is mediated by alterations in the NF-κB pathway with a detected crosstalk between α-solanine treatment and the expression of oxidative stress-responsive miRNAs., (© 2021 Wiley Periodicals LLC.)

Background: Shortage of oxygen is a common condition for residents of high-altitude (HA) areas. In mammals, hemoglobin (Hb) has four derivatives: oxyhemoglobin (Hb-O 2 ), carboxyhemoglobin (Hb-CO), sulfhemoglobin (Hb-S), and methemoglobin (Met-Hb). In HA areas, aberrant physiological performance of blood hemoglobin is well-established., Objectives: The study aimed to investigate the influence of 30 days of HA residence on rabbits' total Hb, Hb derivatives, Hb autooxidation rate, and antioxidant enzymes in comparison to low-altitude control rabbits. Further, the study aimed to investigate the effect of antioxidant-rich Angelica archangelica and/or Ginkgo biloba extracts on the same parameters in HA-resident rabbits., Methods: Rabbits subjected to 30 days of HA residence were compared to low-altitude control rabbits. HA-residence rabbits were then orally administered 0.11 g/kg b.wt. of Angelica archangelica and/or Ginkgo biloba extract for 14 days. Hb derivatives and Hb autooxidation rate were measured spectrophotometrically. Antioxidant enzymes were estimated using specialized kits., Results: Compared to low-altitude rabbits, 30-day HA-residence rabbits showed a noticeable increase (p<0.05) in Hb-O2 and Hb-CO concentration. In addition, Met-Hb concentration, autooxidation rate of Hb molecules, and activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) exhibited a remarkable increase in HA-residence rabbits (p<0.01), reflective of rapid ROS generation. In HA-residence rabbits, both individual and combined treatment with antioxidant-rich extracts for 14 days resulted in recovery to near-normal functional levels of Hb-O2 and Met-Hb, Hb autooxidation rate, and activities of SOD and GPx, while only combined treatment led to Hb-O 2 recovery., Conclusion: The findings suggest that functional Hb levels may be recovered by oral administration of A. archangelica, G. biloba, or combined treatments. In conclusion, oxidative stress due to living in HA areas may be avoided by supplementation with natural antioxidants., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Abelmoschus esculentus (AE) (okra), is an edible plant used in many food applications., Objective: This study explored whether sulfated AE (SAE) has promising cancer chemopreventive activities that may recommend it as a functional food supplement instead of (or in addition to) AE for the population at risk of cancer and in the health food industry., Methods: Cytochrome P450-1A (CYP1A) was estimated by fluorescence enzymatic reaction, using β-naphthoflavone-treated cells (CYP1A inducer). Peroxyl and hydroxyl radical scavenging was assayed by oxygen radical absorbance capacity assay. Flow cytometry was used to analyze apoptosis/necrosis in MCF-7 cells, cell cycle phases in MCF-7 cells, and macrophage binding to fluorescein isothiocyanate-lipopolysaccharide (FITC-LPS). Nitric oxide was determined by Griess assay in LPS-stimulated macrophages, and cytotoxicity was determined by MTT assay. Diethylnitrosamine (DEN) was used to induce hepatic tumor initiation in rats. Placental glutathione-S-transferase (GSTP; an initiation marker) was stained in a fluorescence immunohistochemical analysis of liver sections, and histopathological changes were examined., Results: SAE exhibited strong antitumor initiation and antitumor promotion activities. It suppressed CYP1A, scavenged peroxyl and hydroxyl radicals, induced macrophage proliferation, suppressed macrophage binding to FITC-LPS, inhibited nitric oxide generation, showed specific cytotoxicity to human breast MCF-7 adenocarcinoma cells, and disturbed the cell cycle phases (S and G2/M phases) in association with an increased percentage of apoptotic/necrotic MCF-7 cells. Over a short time period, DEN stimulated liver cancer initiation, but SAE treatment reduced the DEN-induced histopathological alterations and inhibited CYP1A and GSTP., Conclusion: SAE extract has the potential for use as an alternative to AE in health foods to provide cancer chemoprevention in populations at risk for cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Enterolobium cyclocarpum (EC) is an edible plant and a gum source for food industries. Its sulfated polysaccharide extract (SEC) was examined for cancer chemopreventive properties to estimate its anti-tumor activity. The modulation of carcinogen metabolism and the antioxidant activity revealed that SEC is a potent tumor anti-initiator since it inhibited cytochrome P450-1A (CYP1A) and induced carcinogen detoxification enzyme glutathione-S-transferase. SEC is also a weak scavenger for hydroxyl and peroxyl radicals. SEC was found to modulate macrophage functions into an anti-inflammatory pattern, where it enhanced macrophage proliferation and phagocytosis of fluorescein isothiocyanate-lipopolysaccharide (FITC-LPS). In addition, SEC strongly inhibited the nitric oxide (NO) generation in LPS-stimulated macrophages and induced the binding affinity of FITC-LPS to macrophages. SEC exhibited specific cytotoxicity against human hepatocellular Hep G2 carcinoma cells. SEC disturbed the cell cycle phase, as indicated by the concomitant arrest in S- and G2/M-phases that was associated with necrosis induction. A short-term initiation model for liver cancer was prepared using diethylnitrosamine (DEN) in rats. SEC inhibited the DEN-histopathological findings and reduced both CYP1A and the tumor initiation marker placental glutathione S-transferase (GSTP). Taken together, SEC could be used as an alternative gum in health food industries to provide cancer prevention in high-risk populations.

Indole-3-carbinol (I3C) is a naturally occurring glucosinolate found in Brassica vegetables that is usually converted in gastric acidic environment to the efficient metabolite 3,3'-diindolylmethane (DIM). Both indoles (I3C and DIM) are known chemopreventive agents for various cancers including breast cancer. This study aimed to investigate the influence of both indoles on the tumor suppressor miRNAs (let-7a-e, miR-15a, miR-16, miR-17-5p, miR-19a, and miR-20a) and oncomiRs (miR-181a, miR-181b, miR-210, miR-221, and miR-106a), which are controlling the cell cycle key regulators: cyclin-dependent kinases (CDKs), CDK inhibitor p27 Kip1 , and cyclin D1. Our results indicated that both indoles generally elevated the expression of the tumor suppressor miRNAs let-7a-e, miR-19a, miR-17-5p, and miR-20a and decreased the expression of the oncomiR list. Both indoles were able to significantly suppress the expression of CDK4 and CDK6 as well as the apoptotic markers Bcl-2 and survivin. Both indoles decreased cyclin-D1 protein, where I3C decreased cytoplasmic and nuclear cyclin-D1 significantly. Cytoplasmic and nuclear P27 Kip1 showed overexpression following treatment with I3C higher than that detected following DIM treatment. This study provides a mechanistic elucidation of the previously reported cell cycle arrest by I3C and DIM in breast cancer cells suggesting that this effect could be through modulation of miRNAs expression that, in turn, regulates the genetic network controlling the G1/S phase in cell cycle progression.

Epigallocatechin gallate (EGCG), major constituent of green tea, possesses antioxidant, antiviral, and anticancer activities. Gold nanoparticles (AuNPs) play an important role in drug delivery due to their stability, ease of surface functionalization, and unique optical properties. This study aimed to investigate the influence of EGCG-capped AuNPs on tumor suppressor miRNAs (miR-34a and let-7a) and their targeted cell death mediators in HepG2 cells, compared with celastrol. EGCG-AuNPs were prepared and characterized. antioxidant activity was estimated by DPPH scavenging assay; cytotoxicity was assessed by MTT assay; let-7a and miR-34a expression was analyzed by qPCR; and miRNAs targets (c-Myc and caspase-3) were assessed by ELISA and immunocytofluorescence, respectively. The average size of EGCG-AuNPs was 35 nm, with a λmax of ~535 nm. EGCG-AuNPs exerted cytotoxicity on HepG2 cells stronger than that of EGCG alone. EGCG-AuNPs and EGCG presented half-maximal radical scavenging concentrations (SC50) of 539 µg/ml and 45 µg/ml, respectively. The expression levels of let-7a and miR-34a were significantly elevated in HepG2 cells after EGCG-AuNP treatment for 72 h. c-Myc protein expression was reduced, whereas caspase-3 expression was increased following treatment with EGCG-AuNPs. In conclusion, Au-NPs are effective carrier for EGCG, and EGCG-AuNPs are promising anti-cancer agent.

Background: TNFRSF13B, TACI, is a member of the TNF receptor superfamily; it plays a key role in cancer cell proliferation and progression., Method: Influence of silencing of human cytokine receptors on cell viability was screened by Luminescent Cell Viability Assay, after transfection of the siRNA library to find the maximum cell death superhits in both triple-negative MDA-MB-231 and double-positive MCF7 breast cells. The mode of cell death was investigated by dual DNA fluorescence staining. The expression of mRNAs of TACI, BAFF, BAFF-R, and APRIL was explored by qPCR. Immunocytofluorescence analysis was used to evaluate changes in TACI, Bcl-2, TNFR2, cyclin-D2, and PCNA. NF-kB p65, cell cycle, and necrosis/apoptosis (late and early) were analyzed by flow cytometry., Results: TACI is the most potent cytotoxic superhit resulted from high-throughput screening of the siRNA library, in both types of cells. Our findings indicated that silencing receptor TACI in both types of breast cancer cells led to significant cell death, after different intervals from siRNA transfection. Cell death mediators (TNFR2, Bcl-2, and NF-κB) were significantly decreased after TACI silencing. The key factors for cell division (Cyclin-D2 and PCNA) were significantly increased in silenced cells of both types but the cell cycle was arrested before the completion of mitosis. Expression of BAFF, BAFF-R and APRIL mRNA in TACI-silenced cells showed significant upregulation in MDA-MB-231 cells, while only BAFF-R and APRIL showed significant downregulation in MCF7 cells., Conclusion: TACI silencing can be a new and promising therapeutic target for mesenchymal-stem like triple-negative breast cancer subtype., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Lapatinib, one of the tyrosine kinase inhibitors (TKIs), is used to reduce epidermal growth factor family proteins overexpression. This study aims to assess the cytotoxic and genotoxic effects of lapatinib on the triple negative breast cancer cell line "MDA-MB-231". We investigated the cytotoxicity of lapatinib by MTT assay, mode of cell death using apoptosis-necrosis assay, DNA damage using micronucleus test, EGFR protein expression by immunocytochemistry, and assessed its effect on EGFR (7p11.2 locus) and TP53 (17p13 locus) genes using interphase-FISH technique. Lapatinib induced cytotoxicity on MDA-MB-231 cell line by elevating the concentration and its IC 50 value was 32.5 μM after 24 h. Lapatinib increased apoptotic cells and micronuclei in binucleated cells gradually by increasing the concentration for 24 h. The EGFR protein expression was reduced by double fold that expressed in non-treated cells. Lapatinib enhanced deletion of EGFR gene signals highly significantly from the lowest concentration. Alternatively, lapatinib amplified signals of TP53 gene effectively by raising the concentration. In conclusion, lapatinib induced cytotoxic and genotoxic effects on MDA-MB-231 cell line. However, laptinib reduced the EGFR protein expression and EGFR signals, it raised the apoptotic cells and TP53 gene signals, which triggered extensive DNA damage. Therefore, lapatinib is an effective TKI in triple negative breast cancer cells as elucidated by its mode of cell death., (Copyright © 2019. Published by Elsevier B.V.)

Early detection of colorectal cancer and monitoring the progress in colon carcinogenesis stages is essential to reduce mortality. Therefore, there is continuous search for noninvasive biomarkers with high stability and good sensitivity and specificity. miRNAs have attracted attention as promising biomarkers as they are stably expressed in circulation. The aim of our study is to evaluate the aberrant expression of circulating miRNAs during the stepwise progress of colitis-associated colon cancer. This was accomplished through assessing the expression levels of five miRNAs (miR-141, miR-15b, miR-17-3p, miR-21, and miR-29a) in serum and their corresponding tissue samples through the different cycles of colorectal carcinogenesis cascade using the azoxymethane/dextran sulfate sodium murine model. We also compared the diagnostic performance of these selected miRNAs with the conventional tumor biomarkers CEA and CA 19-9. The results of our study revealed that the expression levels of those miRNAs were dynamically changing in accordance with the tumor development state. Moreover, their aberrant expression in serum was statistically correlated with that in tissue. Our data also revealed that serum miR-15b, miR-21, and miR-29a showed the best performance in terms of diagnostic power. Our findings highlight the efficiency of these circulating miRNAs not only for early diagnostics purposes, but also for monitoring progress in the colorectal carcinogenesis process, and therefore encouraging integrating these noninvasive biomarkers into the clinical diagnostic settings beside the traditional diagnostic markers for accurate screening of the early progress of colon carcinogenesis., (© 2019 Wiley Periodicals, Inc.)

Objective: This study aims to investigate the apoptotic effect of Doxorubicin and its nano-formulated form (Doxil) on oral squamous cell carcinoma CAL-27 cells., Design: Cell viability using MTT assay, mode of cell death using fluorescence analysis, expression of the apoptotic marker caspase-3 using indirect ELISA technique and expression of C-Myc gene using reverse transcriptase and real time PCR., Results: Doxil treatment resulted in a higher percentage of apoptotic cells than doxorubicin treatment, while doxorubicin treatment resulted in a higher percentage of necrotic cells than Doxil treatment. Doxil-treated cells exhibited 3.38-fold higher caspase-3 levels than control cells, while doxorubicin significantly increased caspase-3 levels by 2.72-fold. The percentage of C-Myc mRNA inhibition was 27% in doxorubicin-treated cells and 41% in Doxil-treated cells., Conclusions: Doxil exerted a higher apoptotic effect on CAL-27 cells compared to doxorubicin. It showed a higher increase in capase-3 level than doxorubicin and also exerted a more percentage of C-Myc mRNA inhibition., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study focused on kinetics of levan yield by Bacillus subtilis M, in a 150 L stirred tank bioreactor under controlled pH conditions. The optimized production medium was composed of (g/L): commercial sucrose 100.0, yeast extract 2.0, K 2 HPO 4 3.0 and MgSO 4 ⋅7H 2 O 0.2; an increase in both carbohydrates consumption and cell growth depended on increasing the size of the stirred tank bioreactor from 16 L to 150 L. The highest levansucrase production (63.4 U/mL) and levan yield of 47 g/L was obtained after 24 h. Also, the specific levan yield (Y p/x ) which reflects the cell productivity increased with the size increase of the stirred tank bioreactor and reached its maximum value of about 29.4 g/g cells. These results suggested that B. subtilis M could play an important role in levan yield on a large scale in the future. Chemical modifications of B. subtilis M crude levan (CL) into sulfated (SL), phosphorylated (PL), and carboxymethylated levans (CML) were done. The difference in CL structure and its derivatives was detected by FT-IR transmission spectrum. The cytotoxicity of CL and its derivatives were evaluated by HepGII, Mcf-7 and CaCo-2. In general most tested levans forms had no significant cytotoxicity effect. In fact, the carboxymethylated and phosphrylated forms had a lower anti-cancer effect than CL. On the other hand, SL had the highest cytotoxicity showing SL had a significant anti-cancer effect. The results of cytotoxicity and cell viability were statistically analyzed using three-way ANOVA., (Copyright © 2018 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC), however Efficient tissue-specific and safe delivery remains a major challenge., Objective: We sought to develop an inorganic-organic hybrid vehicle for the systemic delivery of the tumor suppressor miR-34a, and to investigate the efficiency of the delivered miR-34a in the treatment of HCC in vitro and in vivo., Methods: In the present study, pEGP-miR cloning and expression vector, expressing miR-34a, was electrostatically bound to polyethyleneimine (PEI), and then loaded onto ZSM-5 zeolite nanoparticles (ZNP). Qualitative and quantitative assessment of the transfection efficiency of miR-34a construct in HepG2 cells was applied by GFP screening and qRT-PCR, respectively. The expression of miR-34a target genes was investigated by qRT-PCR in vitro and in vivo., Results: ZNP/PEI/miR-34a nano-formulation could efficiently deliver into HepG2 cells with low cytotoxicity, indicating good biocompatibility of generated nanozeolite. Furthermore, five injected doses of ZNP/PEI/miR-34a nano-formulation in HCC induced male Balb-c mice, significantly inhibited tumor growth, and demonstrated improved cell structure, in addition to a significant decrease in alphafetoprotein level and liver enzymes activities, as compared to the positive control group. Moreover, injected ZNP/PEI/miR-34a nano-formulation led to a noticeable decrease in the CD44 and c-Myc levels. Results also showed that ZNP/PEI/miR-34a nano-formulation inhibited several target oncogenes including AEG-1, and SOX-9, in vitro and in vivo., Conclusion: Our results suggested that miR-34a is a powerful candidate in HCC treatment and that AEG-1 and SOX-9 are novel oncotargets of miR-34a in HCC. Results also demonstrated that our nano-formulation may serve as a candidate approach for miR-34a restoration for HCC therapy, and generally for safe gene delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: The clinical application of cisplatin is limited by severe side effects associated with high applied doses. The synergistic effect of a combination treatment of a low dose of cisplatin with the natural alkaloid α-solanine on human hepatocellular carcinoma cells was evaluated., Methods: HepG2 cells were exposed to low doses of α-solanine and cisplatin, either independently or in combination. The efficiency of this treatment modality was evaluated by investigating cell growth inhibition, cell cycle arrest, and apoptosis enhancement., Results: α-solanine synergistically potentiated the effect of cisplatin on cell growth inhibition and significantly induced apoptosis. This synergistic effect was mediated by inducing cell cycle arrest at the G2/M phase, enhancing DNA fragmentation and increasing apoptosis through the activation of caspase 3/7 and/or elevating the expression of the death receptors DR4 and DR5. The induced apoptosis from this combination treatment was also mediated by reducing the expression of the anti-apoptotic mediators Bcl-2 and survivin, as well as by modulating the miR-21 expression., Conclusion: Our study provides strong evidence that a combination treatment of low doses of α-solanine and cisplatin exerts a synergistic anticancer effect and provides an effective treatment strategy against hepatocellular carcinoma., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The modulatory role of the Bifidobacterium longum (BL), isolated from women breast milk, on some oncogenic and tumor suppressor miRNAs as well as IL-1β and IL6 targeted-miRNAs was investigated using murine colorectal cancer (CRC) induced on the top of inflammatory ulcerative colitis model. The investigation of the oncomiRs miR-21a and miR-155, which regulate IL-6 and IL-1β expression, indicated that both was depressed by BL-administration in healthy and in CRC-mice. BL-administration induced the tumor suppressor miRNAs (miR-145 and miR-15a) expression in both of the healthy and in CRC-mice. The miR-146a expression, which regulates both of IL-1β and IL-6 expression, was decreased after the BL-administration in both of the healthy and in CRC-mice. In CRC-mice, NF-Kb concentration was elevated, however this NF-Kb induction was diminished after the treatment with BL. BL highly enhanced the IL-1β and IL-6 mRNA and protein concentrations in healthy mice. The administration of BL to CRC-mice resulted in a dramatic increase in IL-1β mRNA and IL-1β concentration, which in contrast was accompanied with a decrease in the IL-6 mRNA and IL-6 concentration. BL-administration resulted in a drop in the aberrant crypt foci number in CRC-mice and increased necrosis and fibrosis of the colon cells. The modulatory influence of B. longum on microRNAs may provide an important therapeutic impact in CRC through inhibition of the proliferation, invasion, apoptosis, and cell cycle of tumor cells.

Photodynamic therapy (PDT) is a non-invasive treatment modality used in the management of both benign and malignant conditions. It involves the administration of a photosensitizing agent followed by local light irradiation, which activates the photosensitizer, resulting in tissue damage. An in-depth understanding of the molecular mechanisms and mediators of PDT is important, not only for appreciating how this treatment modality is effective, but also as an avenue for understanding potential shortfalls and untoward effects that can be managed or improved. MicroRNAs are a group of endogenous small non-coding regulatory molecules that play important roles in regulating several physiological processes and have been implicated in several pathologies including cancer. They have been found to regulate key cellular pathways and their aberrant expression highlights not only disease onset or progression, but is associated with therapy resistance and disease outcome. In the present review, we evaluate the role of microRNAs in PDT and dissect their function as effectors of PDT including the molecules they regulate. We also look at how miRNA signatures can be used as predictors of therapy response to PDT and what implications this may have in the treatment of patients with PDT., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Combretastatin A4 (CA4) is a natural product characterized by a powerful inhibition of tubulin polymerization and a potential anticancer activity. However, therapeutic application of CA4 is substantially hindered due to geometric isomerization. In the current study, new cis-restricted Combretastatin A4 analogues containing 1,2,4-triazle in place of the olefinic bond were designed and synthesized. The synthesized compounds were evaluated for their in vitro antiproliferative activity in human hepatocellular carcinoma HepG2 and leukemia HL-60 cell lines using MTT assay. Moreover, fourteen compounds were selected and tested for their antiproliferative activity by the National Cancer Institute. Some of the tested compounds showed moderate activity against sixty cell lines. In vitro tubulin polymerization inhibitory activity was evaluated on HepG2 cells. The assay revealed that 6a showed a remarkable tubulin inhibition compared to CA4. Moreover, the cell cycle analysis revealed significant G2/M cell cycle arrest of the analogue 6c in HepG2 cells. Molecular docking combined with AMBER-based molecular mechanical minimization results showed several noncovalent interactions, including van der Waals and hydrogen-bonding with several amino acids within the colchicine binding site of β-subunit of tubulin., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Enhancing the cytocompatibility profiles, including cell attachment, growth and viability, of designed synthetic scaffolds, has a pivotal role in tissue engineering applications. Polymer blending is one of the most effective methods for providing new desirable biomaterials for tissue scaffolds. This article reports a novel polyamide 6/poly(ε-caprolactone) (PA6/PCL) blends solution which was fabricated to create composite fibrous tissue scaffolds by varying the concentration ratios of PA6 and PCL. Highly porous blends of fibrous scaffold were fabricated and their suitability as cell-support for EA.hy926 human endothelial cells was studied. Our results demonstrated that the unique nanoscale morphological properties and tune porosity of the blends scaffold were controlled. We found that these properties are mainly dependent on the PA6/PCL blending viscosity value, and the viscosity of the blending solution has an intense effect on the properties of the blends scaffold. The influence of the scaffolds extraction fluids and the scaffold direct contact of both the metabolic viability and the DNA integrity of EA.hy926 endothelial cells, as well as the cell/scaffold interaction analysis by scanning electron microscope, after different co-culturing intervals, demonstrated that PA6/PCL blend scaffolds showed different behaviors. Blend scaffolds of PA6/PCL of 90:10 ratio proved to be excellent endothelial cell carriers, which provided a good cell morphology, DNA integrity and viability, induced DNA synthesis/replication, and enhanced cell proliferation, attachment, and invasion. These results indicate that blends of PA6/PCL composite fibers are a promising 3D substitute for the next generation of synthetic tissue scaffolds that could soon find clinical applications.

Background: In our previous work, we have extensively evaluated the physiochemical characteristics of Gum Arabic-encapsulated gold nanoparticles (GA-AuNPs; 15-18nm) and reported their effectiveness in stopping the tumor initiation via inhibiting the pre-neoplastic lesions in liver., Objective: The rationale of this study is to detect the efficiency of using GA-AuNPs in photothermal application as a non-invasive technique against lung tumor. We investigated the cytotoxicity of GA-AuNPs on A549 cells, and then studied their apoptotic, anti-inflammatory, lipid peroxidation and anti-neovascular effect in in vivo model using a chemically-induced lung cancer in mice. The histopathological changes due to GA-AuNPs were investigated., Results: In the presence of laser irradiation, GA-AuNPs had a considerable cytotoxicity against A549 cells. The treatment of lung tumor-bearing mice with GA-AuNPs followed by laser exposure enhanced the apoptotic pathway and this was obvious from the histopathological investigations and the elevations in cytochrome-c, death receptor 5 and the subsequent upregulation of caspase-3, we also reported a significant reduction in the levels of the inflammatory mediator TNF-α and the angiogenesis inducer VEGF. An induction of lipid peroxidation was also reported upon treatment with either GA or GA-AuNPs., Conclusion: GA-AuNPs showed no cytotoxicity in the absence of light, however the combination of GA-AuNPs with laser induced cell death in lung tumor tissues with a reduction in the inflammation and angiogenesis together with an elevation in lipid peroxidation, suggesting the potential use of these functionalized nanoparticles as a promising photothermal non-invasive treatment modality., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Tubulin targeting agents have received considerable interest as a potential tumor-selective vascular disrupting agents, which represent another avenue for cancer growing therapeutic opportunities. Hence, the present study was conducted to investigate the anti-tumor activity of Combretastatin A-4 phosphate (CA4-P) and vincristine against hepatocellular carcinoma in rats, by individual administration and in combination. In vitro study was conducted using human hepatocellular carcinoma cell lines, showed that CA4-P and vincristine have a potent cell cytotoxic and tubulin inhibitory effect. In addition, a remarkable synergistic effect was observed by the simultaneous application of both drugs. Whereas in vivo study was conducted using model of rat liver cancer initiated with DENA and promoted by CCl 4 , showed that CA4-P and vincristine were significantly decreased liver relative weight, number of hepatic nodules and there relative volumes, tubulin content of the hepatic tissue, GSH and AFP. On the other hand, co-administration of both drugs exhibited significant further decrements in these parameters. Whereas a marked increase in MDA, carbonyl content and TNF-α inside hepatic tissue were observed in the treated groups and these increments were more prominent by co-administration of both drugs. In conclusion CA4-P showed a potential anti-cancer activity against hepatocellular carcinoma and this effect was greatly enhanced by co-administration with vincristine. Additionally, our new findings provided an important evidence that the anticancer activity of drugs with a narrow therapeutic window such as vincristine can be greatly improved by its co-administration with CA4-P providing more enhanced activity with less side effects., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Local delivery of antibiotic into injured bone is a demand. In this work, different scaffolds of chitosan (C) with or without bioactive glass (G) were prepared using the freeze-drying technique in 2:1, 1:1, and 1:2 weight ratios. Chitosan scaffolds and selected formulas of chitosan to bioglass were loaded with ciprofloxacin in 5%, 10%, and 20% w/w. Scaffold morphology showed an interconnected porous structure, where the glass particles were homogeneously dispersed in the chitosan matrix. The kinetic study confirmed that the scaffold containing 1:2 weight ratio of chitosan to glass (CG12) showed optimal bioactivity with good compromise between Ca and P uptake capacities and Si release rate. Chitosan/bioactive glass scaffolds showed larger t 50 values indicating less burst drug release followed by a sustained drug release profile compared to that of chitosan scaffolds. The cell growth, migration, adhesion, and invasion were enhanced onto CG12 scaffold surfaces. Samples of CG12 scaffolds with or without 5% drug induced vascular endothelial growth factor (VEGF), while those containing 10% drug diminished VEGF level. Only CG12 induced the cell differentiation (alkaline phosphatase activity). In conclusion, CG12 containing 5% drug can be considered a biocompatible carrier which would help in the localized osteomyelitis treatment.

This work pointed out the anti-cancer effect of ferrimagnetic glass ceramic nanocomposites (CaO-ZnO-Fe 2 O 3 -SiO 2 ) , which contain high amount of magnetite (∼60%), crystallite size <100nm, and different nucleating agents on bone cancer Saos-2 cells. The cell viability was inhibited by FH and FW to <50% and <25%, respectively, with/without magnetism, and both also reduced mitochondrial transmembrane potential (ΔYm), with/without magnetism (no influence of magnetism). Histone deacetylase (HDAC) activity was inhibited by FH, FW, and FHPNT, with/without magnetism. FHP3/magnetism resulted in HDAC inhibition. In absence of magnetism, FH and FW increased both necrotic and apoptotic cell death, while FW/magnetism induced late apoptosis. DNA fragmentation was increased by FH- and FW-treatment, with/without magnetism. At the same time, FW and FH/magnetism can efficiently induce the intrinsic apoptotic pathway in Saos-2 cells, whereas FW with/without magnetism and FH/magnetism enhanced cytochrome-C release. Similarly, caspase-7 activity was elevated by FH and FW, with/without magnetism. However, the presence of P 2 O 5 in the composition of the nanocomposites inhibited their apoptotic properties and diminished their anti-cancer activity., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

This work investigates and compares the influence of the synthesis process on the in vitro bioactivity of two quaternary bioactive glasses prepared via melting and sol-gel (SG) techniques. The two glasses are named MG and SG, respectively. Powder samples were soaked in simulated body fluid for different time intervals to study the kinetics of Ca and P uptake onto their surface as well as Si release. The uptake kinetics followed the pseudo-second order model, and the kinetic parameters in addition to the initial rates were estimated. MG manifested higher Ca uptake capacity than SG which could be attributed to the presence of a residual organic layer capping the surface of SG, as was confirmed by Fourier transform infrared and nuclear magnetic resonance analyses. However, higher rate of Ca uptake was exhibited by SG probably due to its higher reactivity that resulted from its smaller nano-size and higher negative charge as was evident from transmission electron microscopy and dynamic light scattering measurements, respectively. Furthermore, MG showed slightly higher P uptake capacity and lower amount of Si release. Initial rates of Ca and P uptakes onto SG as well as Si release from SG exceeded those of MG. Human bone osteosarcoma cells (Saos-2) were co-cultured with both MG and SG glasses and the latter showed higher alkaline phosphatase activity and higher cell growth induction. The results showed the promising potential of using both bioactive glasses in bone regeneration. However, the choice of the appropriate bioactive glass depends on the targeted applications.

Background: The photothermal properties of gold nanoparticles (GNPs) are promising therapeutic modality for cancer. The study objective is to evaluate the therapeutic effect of the prepared PEGylated gold nano-semicubes (PEG-GNSCs) in skin cancer. The synthesized PEG-GNSCs were intermediate between cubic and rod shapes (low aspect ratio- rods)., Methods: In vitro toxicity was investigated in human skin melanoma Sk-Mel-28 cells, and skin squamous cell carcinoma was induced in CD1 mice by dimethylbenzanthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)., Results: The calculated IC 50 in Sk-Mel-28 cells was 3.41μg/ml of PEG-GNSCs, in presence of laser exposure. Photothermal therapy using laser-stimulated PEG-GNSCs resulted in inhibited volume of skin tumors. Our findings indicated that the inflammatory mediators, nitric oxide and cycloxygenase-2, were inhibited in mice after being treated with low and high doses of PEG-GNSCs, accompanied with laser exposure. However, the tumor necrosis factor -α was markedly elevated, while there was no change in 5-lipoxygenase. The pro-angiogenic factor vascular endothelial growth factor was inhibited, while histone acetylation and apoptosis were induced in tumor-bearing groups, after being treated with laser-stimulated PEG-GNSCs., Conclusion: The present study indicated the promising photothermal therapeutic effect of laser-stimulated PEG-GNSCs as an effective modality to inhibit the tumor growth, the angiogenesis and partially the inflammation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This study validates the utility of Gum Arabic-conjugated gold nanoparticles (GA-AuNPs) and laser to induce photothermal inhibition of hepatocarcinogenesis, via employing a diethylnitrosamine (DEN)-mediated hepatocellular carcinoma model. This work included both of in vitro and in vivo studies; to investigate the GA-AuNPs cytotoxicity and phototoxicity in hepatic cell line; to delineate the GA-AuNPs therapeutic efficiency in DEN-induced preneoplastic lesions (PNLs) in the liver of Balb-C mice. The therapeutic effects of GA-AuNPs on the mediators of apoptosis, inflammation, and tumor initiation, as well as the histopathological changes in preneoplastic liver have been investigated. Our results infer that GA-AuNPs in combination with laser irradiation led to a significant reduction in the cell viability and in histone deacetylase activity in hepatocarcinoma HepG2 cells. In chemically-induced PNLs mice model our results have demonstrated that GA-AuNPs, with or without laser irradiation, induced cancer cell apoptosis through the activation of death receptors DR5 and caspase-3 and inhibited both of the PNLs incidence and the initiation marker (placental glutathione S-transferase; GST-P). The laser-stimulated GA-AuNPs significantly reduced the tumor necrosis factor-α levels. In summary, GA-AuNPs with laser treatment inhibited liver PNLs via the induction of the extrinsic apoptosis pathway and the inhibition of inflammation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A series of new pyrrol-2(3H)-ones 4a-f and pyridazin-3(2H)-ones 7a-f were synthesized and characterized using different spectroscopic tools. Some of the tested compounds revealed moderate activity against 60 cell lines. The E form of the pyrrolones 4 showed good cytotoxic activity than both the Z form and the corresponding open amide form. Furthermore, the in vitro cytotoxic activity against HepG2 and MCF-7 cell lines revealed that compounds (E)4b, 6f and 7f showed good cytotoxic activity against HepG2 with IC50 values of 11.47, 7.11 and 14.80μM, respectively. Compounds (E)4b, 6f, 7d and 7f showed a pronounced inhibitory effect against cellular localization of tubulin. Flow cytometric analysis indicated that HepG2 cells treated with (E)4b showed a predominated growth arrest at the S-phase compared to that of G2/M-phase. Molecular modeling study using MOE® program indicated that most of the target compounds showed good binding of β-subunit of tubulin with the binding free energy (dG) values about -10kcal/mole., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Nephthea are soft coral species rich in sesquiterpenoids and steroids. An organic extract of Nephthea sp. resulted in the isolation of a new steroid (1), as well as several previously reported metabolites (2-9). Structures were elucidated by employing NMR and HR-EI-MS analyses. The total extract, fractions and purified compounds exhibited differential cytotoxicity against the breast cancer MCF-7 cell line.

Thalidomide has anti-inflammatory, immunomodulatory, and anti-angiogenic properties. It has been used to treat a variety of cancers and autoimmune diseases. This study aimed to characterize anti-inflammatory activities of novel thalidomide analogs by exploring their effects on splenocytes proliferation and macrophage functions and their antioxidant activity. MTT assay was used to assess the cytotoxic effect of thalidomide analogs against splenocytes. Tumor necrosis factor (TNF-α) and nuclear factor kappa B (NF-κB-P65) were determined by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) was estimated by colorimetric assay. Antioxidant activity was examined by ORAC assay. Our results demonstrated that thalidomide dithioate analog 2 and thalidomide dithiocarbamate analog 4 produced a slight increase in splenocyte proliferation compared with thalidomide. Thalidomide dithiocarbamate analog 1 is a potent inhibitor of TNF-α production, whereas thalidomide dithiocarbamate analog 5 is a potent inhibitor of both TNF-α and NO. Analog 2 has a pronounced inhibitory effect on NF-κB-P65 production level. All thalidomide analogs showed prooxidant activity against hydroxyl (OH) radical. Analog 1 and thalidomide dithioate analog 3 have prooxidant activity against peroxyl (ROO) radical in relation to thalidomide. On the other hand, analog 4 has a potent scavenging capacity against peroxyl (ROO) radical compared with thalidomide. Taken together, the results of this study suggest that thalidomide analogs might have valuable anti-inflammatory activities with more pronounced effect than thalidomide itself., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

A series of novel 5-(substituted phenyl)-3-[(substituted phenylamino)methyl]-3H-[1,3,4]oxadiazole-2- thione derivatives were prepared and their in vitro cytotoxicity was evaluated against a panel of three cancer cell lines, namely, hepatocarcinoma HepG2, breast adenocarcinoma MCF-7, and leukemia HL-60 cells, using the widely accepted MTT assay. In general, the synthesized compounds displayed weak to moderate cytotoxic activity against the three tested cell lines. Compound 5a, which has trimethoxy substituents on both phenyl rings, exhibited the highest cytotoxic effect against all cell lines tested with IC50 values of 12.01, 7.52 and 9.7 μM against HepG2, MCF-7 and HL-60 cells, respectively. Mechanistic studies revealed that the test compounds showed a good inhibitory effect on cellular tubulin of hepatocellular carcinoma. Compound 5h was the most potent tubulin inhibitor in HepG2 cells, with 81.1 % inhibition of the original control tubulin. Moreover, the mechanism of tubulin polymerization inhibition was confirmed by immunofluorescence assay, flow cytometry, and docking study.