CRISPR-Cas9 genome and long non-coding RNAs as a novel diagnostic index for prostate cancer therapy via liposomal-coated compounds.

CRISPR/Cas9 is a recently discovered genomic editing technique that altered scientist's sight in studying genes function. Cas9 is controlled via guide (g) RNAs, which match the DNA targeted in cleavage to modify the respective gene. The development in prostate cancer (PC) modeling directed not only to novel resources for recognizing the signaling pathways overriding prostate cell carcinoma, but it has also created a vast reservoir for complementary tools to examine therapies counteracting this type of cancer. Various cultured somatic rat models for prostate cancer have been developed that nearly mimic human prostate cancer. Nano-medicine can passively target cancer cells via increasing bioavailability and conjugation via specific legend, contributing to reduced systemic side-effects and increased efficacy. This article highlights liposomal loaded Nano-medicine as a potential treatment for prostate cancer and clarifies the CRISPR/Cas9 variation accompanied with prostate cancer. PC is induced experimentally in western rat model via ethinyl estradiol for 4 weeks and SC. dose of 3, 2'- dimethyl-4-aminobiphenyl estradiol (DAE) (50mg/kg) followed by treatment via targeted liposomal-coated compounds such as liposomal dexamethasone (DXM), liposomal doxorubicin (DOX) and liposomal Turmeric (TUR) (3mg/kg IP) for four weeks in a comparative study to their non-targeted analogue dexamethasone, doxorubicin and Turmeric. 3, 2'- dimethyl-4-aminobiphenylestradiol elicit prostate cancer in western rats within 5 months. Simultaneous supplementations with these liposomal compounds influence on prostate cancer; tumor markers were investigated via prostate-specific antigen (PSA), Nitric oxide (NOX) and CRISPR/Cas9 gene editing. Several long non-coding RNAs were reported to be deregulated in prostate cell carcinoma, including MALAT1. On the other hand, gene expression of apoptotic biomarkers focal adhesion kinase (AKT-1), phosphatidylinistol kinase (PI3K) and glycogen synthase kinase-3 (GSK-3) was also investigated and further confirming these results via histopathological examination. Liposomal loaded dexamethasone; doxorubicin and Turmeric can be considered as promising therapeutic agents for prostate cancer via modulating CRISPR/Cas9 gene editing and long non coding gene MALAT1.

Alleviation of doxorubicin adverse effects via loading into various drug-delivery systems: a comparative study.

Aim: Drug resistance is still a significant barrier to effective hepatocellular carcinoma therapy. Address the issue of doxorubicin resistance and inter-receptor crosstalk various doxorubicin formulations were investigated. Methods: Hepatocellular carcinoma was carried out using 3-methylechloroanthrene. Animals were then treated with doxorubicin, liposomal doxorubicin, titanium-loaded doxorubicin (TiO2-Dox), lactoferrin-doxorubicin and PEGylated doxorubicin. Biochemical and molecular analyses were assessed. Results: Results have declared a significant alternation of both sodium and potassium concentrations upon 3-methylechloroanthrene administration. Arginase-I and α-L-Fucodinase tumor biomarkers were significantly elevated. C-myc, Hprt-1 and EGFR gene expression were over-expressed. Treatment with the aforementioned treatment regimens significantly modulated all measured parameters. Conclusion: TiO2-Dox, doxorubicin-lactoferrin and PEGylated doxorubicin could be a promising regimen in hepatocellular carcinoma and overcoming the problem of drug resistance.

Amelioration of autophagy and inflammatory signaling pathways via α-lipoic acid, burdock and bee pollen versus lipopolysaccharide-induced insulin resistance in murine model.

Lipopolysaccharide (LPS) has previously been implicated in insulin resistance by generating an innate immune response and activating inflammatory cascades. Many studies have discovered a relationship between high levels of serum LPS and the advancement of diabetic microvascular problems, indicating that LPS may play a role in the control of critical signaling pathways connected to insulin resistance. The current study focused on signaling pathways linked to insulin resistance and explored probable mechanisms of LPS-induced insulin resistance in a murine model. It next looked at the effects of burdock, bee pollen, and -lipoic acid on LPS-induced inflammation and autoimmune defects in rats. LPS intoxication was induced via ip injection for one week in a dose of 10 mg/kg followed by α-lipoic acid, Burdock and bee pollen in an oral treatment for one month. Following that, biochemical and molecular studies were performed. The RNA expression of the regulating genes STAT5A and PTEN was measured. In addition, ATF-4 and CHOP as autophagy biomarkers were also subjected to mRNA quantification. The results demonstrated a considerable improvement in the -lipoic acid, Burdock, and bee pollen treated groups via modifying oxidative stress indicators as well as molecular ones. Furthermore, glucose concentration in serum and α-amylase were also improved upon treatment with the superiority of α-lipoic acid for modulating all estimated parameters. In conclusion: the results declared in the current study suggested that α-lipoic acid could regulate insulin resistance signaling pathways induced by LPS intoxication.

Therapeutic impact of purified Trichoderma viride L-asparaginase in murine model of liver cancer and in vitro Hep-G2 cell line.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the common cancers, but difficult to diagnose and treat. L-asparaginase has been introduced in the treatment protocol of pediatric acute lymphoblastic leukemia (ALL) since the 1960s with a good outcome and increased survival rates to nearly 90%. Moreover, it has been found to have therapeutic potential in solid tumors. Production of glutaminase-free-L-asparaginase is of interest to avoid glutaminase-related toxicity and hypersensitivity. In the current study, an extracellular L-asparaginase that is free of L-glutaminase was purified from the culture filtrate of an endophytic fungus Trichoderma viride. The cytotoxic effect of the purified enzyme was evaluated in vitro against a panel of human tumor cell lines and in vivo against male Wister albino mice intraperitoneally injected with diethyl nitrosamine (200 mg/kg bw), followed by (after 2 weeks) oral administration of carbon tetrachloride (2 mL/kg bw). This dose was repeated for 2 months, and after that, the blood samples were collected to estimate hepatic and renal injury markers, lipid profiles, and oxidative stress parameters. RESULTS: L-asparaginase was purified from T. viride culture filtrate with 36 purification folds, 688.1 U/mg specific activity, and 38.9% yield. The highest antiproliferative activity of the purified enzyme was observed against the hepatocellular carcinoma (Hep-G2) cell line, with an IC50 of 21.2 g/mL, which was higher than that observed for MCF-7 (IC50 34.2 g/mL). Comparing the DENA-intoxicated group to the negative control group, it can be demonstrated that L-asparaginase adjusted the levels of the liver function enzymes and the hepatic injury markers that had previously changed with DENA intoxication. DENA causes kidney dysfunction and altered serum albumin and creatinine levels as well. Administration of L-asparaginase was found to improve the levels of the tested biomarkers including kidney and liver function tests. L-asparaginase treatment of the DENA-intoxicated group resulted in a significant improvement in the liver and kidney tissues to near normal similar to the healthy control group. CONCLUSION: The results suggest that this purified T. viride L-asparaginase may be able to delay the development of liver cancer and may be used as a potential candidate for future application in medicine as an anticancer medication.

Ki-67 pulmonary immunoreactivity in silver nanoparticles toxicity: Size-rate dependent genotoxic impact.

Engineered nanoparticles have been recently utilized in numerous domains particularly, silver nanoparticles (AgNPs). Nonetheless, the possible side effects resulting from AgNPs exposure are not fully clarified. The present study was designed to clarify the toxicity of AgNPs on lung tissue. Furthermore, therapeutic impact of Glycosmis pentaphylla (G. pentaphylla) and Casimiroa edulis (C. edulis) leaves extracts in addition to mucilage and protein (the purified compounds from C. edulis) was investigated against AgNPs induced pulmonary toxicity. Male Swiss albino mice were administered AgNPs orally in two different particle sizes (20 nm and 100 nm) for one month and was further treated via G. pentaphylla, C. edulis, mucilage and protein in a dose of 500 mg/ kg for three weeks. Biochemical, molecular, immunohistochemistry, and histopathological investigations were further assessed. An obvious alteration in oxidative stress biomarkers as well as mRNA gene expression of both survivin and matrix metalloproteinase (MMP-9) was recorded in AgNPs intoxicated group. In addition to, exploration of positive nuclei for Ki-67 was also observed upon AgNPs intoxication. Data declared a significant improvement in the assessed parameters upon G. pentaphylla, C. edulis, mucilage and protein treatment. In conclusion; G. pentaphylla and C. edulis extracts could be considered as a promising candidate as therapeutic regimen against pulmonary toxicity induced via AgNPs due to their enrichment with different active constituents. Practical applications: Due to the expansion of AgNPs applications, it is urgent to investigate their toxic impact associated with release of free silver ions. Different particle sizes of AgNPs can induce various alterations in cellular biochemical parameters, mRNA gene expression, histopathological and immunohistopathological examination. Herein, this natural products extracts are used for the first time as promising therapeutic regimen to ameliorate the toxic effect in AgNPs intoxicated lung tissue in mice model as a result of the bioactive metabolites, especially flavonoids and polyphenolic compounds.

Mitigation of apoptosis-mediated neurotoxicity induced by silver nanoparticles via rutaceae nutraceuticals: P53 activation and Bax/Bcl-2 regulation.

Rapid progress in nano-scales and nanostructure extremely altered the way of diagnosing or preventing numerous diseases. One of the most important nano-medicines used in cancer treatment and diagnosis is silver nanoparticles (AgNPs). Regardless of their extensive utilization, their prospective neurotoxicity wasn't studied yet. Herein, male Swiss Albino mice were intoxicated via two Nano-scales of AgNPs; (20 nm and 100 nm) for one month (100 mg/kg) then treated by leaves extracts of both Casimiroa edulis (C. edulis) and Glycosmis pentaphylla (G. pentaphylla), in addition to, mucilage and protein, the separated compounds from C. edulis fruits and seeds respectively in a dose of (500 mg/kg). Molecular, Biochemical and histopathological examinations were then conducted. Data recorded showed a significant elevation in hydrogen peroxide (H2O2) level and reduction in glutathione peroxidase (GPX) level post AgNPs intoxication. The oxidative stress occurred was modulated upon treatment regimens. Protein expression of C-reactive protein (CRP) showed a significant elevation and Molecular analysis recorded a significant up-regulation in the expression of both Bax and caspace-3 genes upon AgNPs intoxication in both particles size. On the contrary, both Bcl2 and P53 gene expression were shown to be significantly reduced. Treatment by C. edulis, G. pentaphylla, protein and mucilage extracts revealed modulation in apoptotic and pro-apoptotic biomarkers. Histopathological examination confirmed the obtained results. AgNPs exposure could induce neurotoxicity, genetic alternation and oxidative stress; the targeted extracts could be considered as a promising candidate in modulating apoptosis and neurotoxicity induced by AgNPs.

Insights on attenuating autophagy cellular and molecular pathways versus methotrexate-induced toxicity via liposomal turmeric therapy.

BACKGROUND: Methotrexate (MX), a competitive inhibitor of dihydrofolate reductase, can inhibit DNA and RNA production and is a powerful anticancer agent widely utilized in clinical practice for treating nonneoplastic maladies, as psoriasis and rheumatoid arthritis; meanwhile, its probable prescription dose and interval of administration are strictly limited due to dose-related organ damage. Former studies verified that kidney, brain, liver, and lung harms are prospective obstacles of methotrexate administration. To understand the machinery of methotrexate-prompt toxicity, various mechanisms were investigated. The former is an autophagy defense mechanism; autophagy is a self-digesting mechanism responsible for the removal of damaged organelles and malformed proteins by lysosome. The contemporary article hypothesized that turmeric or its liposomal analog could defeat autophagy of MX-induced acute toxicity. Methotrexate, in a dose of 1.5 mg/kg, was administered intravenously followed by turmeric and liposomal turmeric treatment in a dose of 5 mg/kg for 30 days in rats. RESULTS: Increment in autophagy (AUTP) consent by MX administration was attenuated by concurrent treatment via turmeric and liposomal turmeric that was reliable on the alteration in apoptotic markers. The assembly of FOXO-3 in serum post methotrexate administration was suppressed by concurrent treatment via liposomal turmeric. Apoptosis/autophagic marker investigation was evaluated through the gene expression of Bax (BCL2-associated X protein)/Bcl2 (B-cell lymphoma 2)/P53 (tumor protein P53)/SiRT-1 (sirtuin silent mating-type information regulation 2 homolog 1) and FOXO-3 (forkhead box transcription factor-3)/ERDJ-4 (endoplasmic reticulum localized DnaJ homologs)/BNP (brain natriuretic peptide B) signaling. The cell death of all cells was categorized to achieve autophagy. Interestingly, Bax/Bcl2/P53/SiRT-1 signaling pathways were downregulated, contributing to inhibiting the initiation of autophagy. Meanwhile, FOXO-3/BNP/ERDJ-4 reduction-implicated noncanonical autophagy pathways were involved in methotrexate-induced autophagy, whereas this change was suppressed when turmeric was administered in liposomal form. CONCLUSION: These outcomes recommended that liposomal turmeric prevents MX-induced acute toxicity through its autophagy, antioxidant, and antiapoptotic properties.

Ubiquitous toxicity of Mercuric Chloride in target tissues and organs: Impact of Ubidecarenone and liposomal-Ubidecarenone STAT 5A/ PTEN /PI3K/AKT signaling pathways.

BACKGROUND: Mercuric chloride (HgCl3) is categorized as class II B hazardous metal that is present in many occupational and environmental conditions. In the meantime, Hg exists in the environment in such an abundant manner, it is virtually impossible for humans to avoid exposure to different forms of Hg. In addition to environmental exposure, individuals may be exposed to Hg from dental amalgams, medicinal treatments and dietary sources. Nevertheless, Liposomal drug delivery system is a promising era in the field of Nano-medicine and have the advantageous of increasing drug bioavailability and retention phenomena in addition to targeting organ for all mentioned the present study was designed to investigate the hypothesis that messenger RNA gene expression of Signal transducer and activator of transcription- 5 A (STAT-5A), Phosphatase and tensin homolog (PTEN), phosphoinositol kinase (PI3K) and alpha serine/threonine-protein kinase (AKT) can trigger HgCl3 induced nephrotoxicity post Ubidecarenone and liposomal Ubidecarenone therapy. METHODS: HgCl3 toxicity was induced in rats via a dose of 5 mg/kg BW for one week followed by Ubidecarenone and liposomal Ubidecarenone therapy in a dose of 10 & 3 mg/kg BW for one month, respectively. Then kidney function tests, Glutathione and gene expression for PI3K, AKT, PTEN and STAT-5A was investigated. RESULTS: HgCl3 intoxication significantly up regulated PI3K, AKT, PTEN and STAT-5A signaling pathways meanwhile, Ubidecarenone and liposomal- Ubidecarenone treatment significantly reduced PI3K, AKT, PTEN and STAT-5A gene expression post HgCl3 intoxication with the liposomal regimen revealing the most significant impact. Furthermore, renal toxicity was confirmed via monitoring urea and creatinine which were modulated post Ubidecarenone and liposomal-Ubidecarenone treatment. Wide evidence declared that mercuric S-conjugates of small endogenous thiols (such as Hcy, NAC and Cys) are probably the main transportable forms of Hg2+ to the kidneys thus reduced glutathione was investigated which reflected a significant down regulation post Hgcl3 toxicity. CONCLUSION: liposomal drug delivery system including liposomal-Ubidecarenone can be considered as a prospective candidate for treating HgCl3 renal toxicity via modulating STAT-5A, PTEN, PI3K and AKT signaling pathways and via increasing retention time, bioavailability, shielding from macrophage recognition and targeting organs.

Probiotics: a Promising Generation of Heavy Metal Detoxification.

Different environmental toxins especially heavy metals exist in soil, water, and air recording toxic effect on human, animal, and plant. These toxicant elements are widespread in environment causing various disturbances in biological systems. Numerous strategies have been applied recently to alleviate heavy metal contamination; however, most of these strategies were costly and seemed unfriendly to our environment. Probiotics are living cell bacteria with beneficial characteristics for human health. Lactobacillus and Bifidobacterium are the major probiotic groups; however, Pediococcus, Lactococcus, Bacillus, and yeasts are recorded as probiotic. The vital role of the probiotics on maintenance of body health was previously investigated. Probiotics were previously recorded to its powerful capacity to bind numerous targets and eliminate them with feces. These targets may be aluminum, cadmium, lead, or arsenic. The current review discusses the history of probiotics, detoxification role of probiotics caused by heavy metals, and mechanism of their action that modulate different signaling pathway disturbance associated with heavy metal accumulation in biological system.

Crosslink among phosphatidylinositol-3 kinase/Akt, PTEN and STAT-5A signaling pathways post liposomal galactomannan hepatocellular carcinoma therapy.

Liposomal drug-delivery systems (LDDs) provide a promising opportunity to precisely target organs, improve drug bioavailability and reduce systemic toxicity. On the other hand, PI3K/Akt signaling pathways control various intracellular functions including apoptosis, invasion and cell growth. Hyper activation of PI3K and Akt is detected in some types of cancer that posses defect in PTEN. Tracking the crosstalk between PI3K/Akt, PTEN and STAT 5A signaling pathways, in cancer could result in identifying new therapeutic agents. The current study, identified an over view on PI3K/Akt, PTEN and STAT-5A networks, in addition to their biological roles in hepatocellular carcinoma (HCC). In the current study galactomannan was extracted from Caesalpinia gilliesii seeds then loaded in liposomes. Liposomes were prepared employing phosphatidyl choline and different concentrations of cholesterol. HCC was then induced in Wistar albino rats followed by liposomal galactomannan (700 ± 100 nm) treatment. Liver enzymes as well as antioxidants were assessed and PI3K/Akt, PTEN and STAT-5A gene expression were investigated. The prepared vesicles revealed entrapment efficiencies ranging from 23.55 to 69.17%, and negative zeta potential values. The optimum formulation revealed spherical morphology as well as diffusion controlled in vitro release pattern. Liposomal galactomannan elucidated a significant reduction in liver enzymes and MDA as well as PI3K/Akt, PTEN and STAT 5A gene expression. A significant elevation in GST and GSH were deduced. In conclusion, Liposomal galactomannan revealed a promising candidate for HCC therapy.

DNA damage and genetic aberration induced via different sized silver nanoparticles: Therapeutic approaches of Casimiroa edulis and Glycosmis pentaphylla leaves extracts.

Potential of Casimiroa edulis and Glycosmis pentaphylla leaves extracts were investigated against the effect of two different particle sizes of silver nanoparticles induced toxicity in mice. Mice received silver nanoparticles (AgNPs) (100 mg/kg) with 20 and 100 nm for four weeks followed by daily oral dose of extracts (500 mg/kg) for three weeks. C. edulis leaves identified fourteen phenolic compounds while, G. pentaphylla leaves identified, twelve phenolic compounds. Additionally, biochemical, genotoxicity, mutagenicity, and histopathological investigations were carried out, revealed that liver function activities, lipid profile, hydrogen peroxide, and C-reactive protein were significantly elevate post AgNPs exposure. While, superoxide dismutase, glutathione-S-transferases, and glutathione peroxidase significantly reduce. A marked amelioration in all detected biomarkers, improved histopathological changes and repair DNA damage after treated with C. edulis and G. pentaphylla leaves extracts. These extracts are used for the first time as promising candidate therapeutic agents against toxicity induced by AgNPs. PRACTICAL APPLICATIONS: The potential applications of AgNPs make it necessary to investigate the possible toxicity associated with release of free silver ions in the biological system. AgNPs of varying particle sizes had toxic effects as evidenced by alterations in some cellular biochemical parameters, genotoxicity, mutagenicity, and histopathological indices on mice. Casimiroa edulis and Glycosmis pentaphylla leaves extracts are used for the first time as promising candidate therapeutic, where they are able to ameliorate the toxicity induced via AgNPs and record vacillate percentage of improvement in the selected biomarkers, as a result of the bioactive secondary metabolites especially flavonoids and other polyphenolic compounds.

Hyssopus officinalis exerts hypoglycemic effects on streptozotocin-induced diabetic rats via modulating GSK-3ß, C-fos, NF-κB, ABCA1 and ABGA1 gene expression.

OBJECTIVES: Type 2 diabetes mellitus (DMT2) is contributed to dual interactions between environmental factors and certain genetic factors. This impressed a great need for novel treatment strategy. Nevertheless, Hyssopus officinalis (H. officinalis) as a terrestrial herb is considered to be an important source of natural antioxidants, it could be assessed as an anti-hyperglycemic agent. METHODS: In the current study, HPLC identified the active constitutes of H. officinalis, including total polyphenols, and flavonoids. Type 2 diabetes mellitus was induced in male Wistar albino rats via a single ip dose of streptozotocin (STZ) (35 mg/kg BW). One week post diabetes induction, rats were administrated H. officinalis (500 mg/ kg BW) orally for one month. Molecular analysis was assessed to investigate the efficiency of H. officinalis on modulating ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) genes, in addition to apoptotic biomarkers, glycogen synthase kinase-3ß (GSK-3ß) and cellular oncogene-fos (C-fos) genes. Furthermore, inflammatory biomarkers, nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) gene expression were also assessed. RESULTS: H. officinalis alcoholic extract declared the presence of polyphenols as gallic acid and flavonoids as quercetin in addition to many active constituents. Apigenin-7-glucoside and Chlorgenic acid were the most common constituents in the extract. RT-PCR results declared a significant up-regulation in mRNA gene expression of ABCA1 and ABCG1 upon H. officinalis treatment. Meanwhile, C-fos gene expression recorded a slight down-regulation. Gene expression of apoptotic biomarker GSK-3ß demonstrated a significant down regulation as well as inflammatory biomarkers NF-κB and TNF-α. CONCLUSION: From the data recorded, it could be concluded that H. officinalis exerts a great hypoglycemic potential via modulating C-fos, GSK-3ß, NF-κB, TNF-α, ABCA1 and ABCG1 gene expression and signaling pathways and could be considered as an effective candidate for DMT2 treatment.

Antimicrobial activity and acetylcholinestrase inhibition of novel synthesized pyrimidine derivatives versus Candida albicans trafficking to brain and kidney.

The expedient fungi Candida albicans (C. albicans) is able to thrive in many host niches including blood stream, skin, mucosal surfaces, and different body organs. Herein, the assessment of novel synthesized pyrimidine derivatives as anti fungal agent was investigated. Female albino mice were injected intraperitoneally by C. albicans (1.5 × 106 CFU). infected Mice then subjected to treatment with two different doses which was low (50 mg/kg) and high one (200 mg/kg) of diflucan in addition to the newly synthestic compounds (2-(4- (Pyridine- 2- yl) aminosulfonyle phenylamino) - 6 -(naphthalene-2- yl)-4-(pyridine-2- yl) n - 3 carbonitril) and (2-(4-(Pyrimidine-2- yl) aminosulfonyle phenylamino)- 6 -(naphthalene-2- yl)- 4 -(pyridine-2- yl) pyridine-3- carbonitril) donated as (C1 & C2, respectively). Three weeks later gene expression of renal alpha smooth muscle actin (α-SMA) and of cyclooxygenase-2 (COX-2) protein expression were assessed as well as serum malondialdehyde (MDA) and total antioxidant capacity in both kidney and brain tissues. Furthermore, acetylcholinestrase activity was assessed. Candida albicans significantly elevated serum MDA. On the other hand, C. albicans injection revealed a significantly reduction in total antioxidant capacity in kidney as well as in brain tissue. Furthermore, acetylcholine assessment declared a significant elevation. All biochemical parametersÛ¥ upset were modulated upon new synthesized compounds treatment. Molecular analyses declared a significant down - regulation in renal α -smooth muscle actin gene expression in addition to, a significant down- regulation in COX-2 protein expression. From data recorded, it could be concluded that, C2 in a dose 200 mg ∕kg noticeably declared a significant effect comparing with the other treated groups revealing its promising effect as anti-fungal agent.

Regulation of apoptotic and inflammatory signaling pathways in hepatocellular carcinoma via Caesalpinia gilliesii galactomannan.

A polysaccharide characterized as galactomannan (GMann) with a molecular weight of 117.76 kDa was isolated from the aqueous extract of Caesalpinia gilliesii (C. gilliesii) seeds then assessed for antiproliferative potential against human hepatocellular carcinoma cell line (HepG2). Further, HCC was induced in Wister albino rats by Diethylnitrosamine (DEN) ip injection (200 mg/kg bw), and CCl4 orally (2 ml/kg bw) for two months then subjected to GMann orally treatment (2 mg/kg bw) for one month. In results, isolated GMann is constituted of sugars (89.99 ± 2.3%), moisture (6.89 ± 0.45%), ash (0.06 ± 0.2%), and protein (2.81%) and composed mainly of mannose and galactose in ratio M/G 3.79. In vitro study, data revealed a concentration-dependent potency of GMann to induce cell death of HepG2 cells with IC50 value of 0.375 µg/ml. Mechanistic studies revealed the potential of GMann to arrest cell cycle at G2/M phase with induction of apoptosis. Biochemical results in vivo showed a significant reduction in serum transaminases (ALT and AST) as well as hepatic malondialdehyde (MDA) and nitric oxide (NOx). Molecular analysis declared a significant down-regulation in mRNA gene expression of both nuclear factor kappa-B (NF-κB) and tumor necrosis factor (TNF-α). Furthermore, a significant down-regulation in the cellular oncogene-fos (C-fos) and marked up-regulation in Glycogen synthase kinase-3 (GSK-3ß) level were observed. These results were supported with histopathological investigation. Whereas GMann improved inflammatory and apoptotic markers, it could be a promising new therapeutic agent for HCC suppression and this warrant further development as a possible drug candidate for HCC.

Crosstalk between GSK-3, c-Fos, NFκB and TNF-α signaling pathways play an ambitious role in Chitosan Nanoparticles Cancer Therapy.

Nanotechnology is a promising era of medicine for developing targeted drug delivery system. Chitosan nanoparticles (CNPs) have attracted increasing attention for their wide applications as anticancer drugs. This article is concerned with the therapeutic index of chitosan nanoparticles against diethyl nitrosamine (DEN) induced hepatocellular carcinoma (HCC). HCC was induced in rats via repeated DEN administration in a dose of 200 mg/kg BW IP, 2 weeks later rats received (2 ml/kg BW) CCl4 orally for 2 months followed by daily treatment with chitosan nanoparticles in an oral dose of 12 mg/kg for 1 month. Then the gene expression of glycogen synthase kinase-3 (GSK-3), (c-FOS), nuclear factor kappa-B (NFκB) and tumor necrosis factor- α (TNF-α) were reported in rats sera and the correlation between GSK-3, C-Fos, NFƘB and TNF-α and liver tumorigenesis was investigated. The results elucidated that DEN significantly increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Marked increments in serum malondialdehyde (MDA) and nitric oxide (NOx) levels along with a slight reduction of glutathione (GSH) level were evidenced in HCC. Liver injury triggered an inflammatory response by enhancing the mRNA gene expression of NFκB and TNF-α. DEN effectively activated apoptotic markers GSK-3 and c-FOS. Oral administration of CNPs alleviated the oxidative, inflammatory and apoptotic hazards induced via DEN. The histopathological examination reinforced these results. The present study highlights the anti-inflammatory and anti-apoptotic potentials of CNPs against DEN-induced HCC.

Modulation of Cyp450, ALS1 and COX-2 signaling pathways induced by Candida albicans infection via novel antifungal agents.

Although, fluconazole is widely used in clinical treatment as an antifungal drug, it recorded potential problems as resistance and intracellular accumulation. Female albino mice were injected with single ip dose of Candida albicans (1.5 × 106 CFU). Three weeks post treatment with fluconazole and two novel synthesized compounds [(2-(4-(Pyridin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridin-2-yl) pyridine-3carbonitrile) and (2-(4-(Pyrimidin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridine-2-yl)pyridine-3-carbonitrile) (13b & 14b, respectively)] in both low and high doses (50 mg/kg & 200 mg/kg), liver function and vaginal inflammation were assessed. Candida albicans significantly elevated serum alanine aminotransferase (ALT) and butrylcholinesterase (BCHE) as well as hepatic malondialdehyde (MDA). Molecular analysis confirmed a significant up-regulation in mRNA gene expression of Agglutinin-like sequence (ALS1), hepatic cytochrome p450 (Cyp450). Vaginal COX-2 gene expression was also elevated. Nevertheless, a significant down-regulation was apparent in mice treated with the aforementioned compounds. Meanwhile, administration of 14b in a high dose noticeably down-regulated the altered parameters expression showing a significant effect in comparison to animals treated with the variable doses of the tested compounds. Histopathological finding confirmed the obtained results. The current work investigated the efficiency of new synthetic pyrimidine derivatives 14bas anti-microbial agents and recommended to be improved and evaluated as a novel antifungal drug to overcome the emergence of resistance problem.

Novel Mesenchymal Stem Cell Strategy in Alleviating Toll-Like Receptor-4, p53 and Nrf2 Signaling in Isoproterenol-Induced Myocardial Infarction in Rat Model.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that merit the differentiation into various cell types. The present study was designed to test the hypothesis that the cardioprotective effect of MSCs transplantation and digoxin treatment is mediated via the regulation of messenger RNA gene expression of pro-inflammatory cytokines and apoptotic markers. Myocardial infarction was induced in Wistar rats via isoproterenol injection in a dose of (85 mg/kg, subcutaneously, twice at an interval of 24 h). Four weeks post-MSCs transplantation and digoxin treatment a significant reduction in serum cardiac markers, aspartate aminotransferase, creatine kinase-MB and troponine II was observed. Meanwhile, isoproterenol significantly reduced the gene and protein expression of the oxidative stress marker nuclear-related factor-2 (Nrf2) with a concomitant elevation in (MDA) level and inflammatory markers toll-like receptor-4 (TLR-4), intercellular adhesion molecules (ICAMs) and (VCAM-1). Moreover, apoptotic marker (P53) was significantly down-regulated. This was confirmed by histopathological investigations. It was hypothesized that MSCs transplantation was superior over digoxin treatment regimen in improving heart function.

Bone marrow-derived mesenchymal stem cells mitigate caspase-3 and 8-hydroxy proline induced via ß-adrenergic agonist in pulmonary injured rats.

Estimating the ability of bone marrow-derived mesenchymal stem cells (BM-MSCs) to alleviate pulmonary injury induced via isoproterenol (ISP). ISP was injected in a dose of (100 mg/kg, subcutaneously twice at an interval of 24 h). One month post BM-MSCs transplantation by intravenous injection, pulmonary oxidative stress was assessed, and Western blot analyses and histopathological investigations were conducted. Compared with the normal control group, BM-MSCs transplantation significantly decreased the expression of pulmonary anti-oxidative stress marker. Western blot analysis revealed that ISP significantly reduced the protein expression of the anti-oxidative stress marker nuclear related factor-2 (Nrf2). However, the apoptotic marker (caspase-3) and collagen content marker (8-hydroxyproline) were markedly elevated. These biochemical markers were confirmed by histopathological investigations. Finally, it was demonstrated that BM-MSCs transplantation showed a superior effect in improving pulmonary function through alleviating oxidative stress, apoptosis, and collagen content.