Glabratephrin reverses doxorubicin resistance in triple negative breast cancer by inhibiting P-glycoprotein.

Triple-negative breast cancer is one of the most aggressive breast cancer. The first therapeutic option is chemotherapy, often based on anthracycline as doxorubicin. However, chemotherapy efficacy is limited in by the presence of P-glycoprotein (Pgp), a membrane transporter protein that effluxes doxorubicin, reducing its cellular accumulation and toxicity. Inhibiting Pgp activity with effective and non-toxic products is still an open challenge. In this work, we demonstrated that the natural product Glabratephrin (Glab), a prenylated flavonoid from Tephrosia purpurea with a unique chemical structure, increased doxorubicin accumulation and cytotoxicity in triple negative breast cancer cells with high levels of Pgp, characterized by both acquired or intrinsic resistance to doxorubicin. Glab also reduced the growth of Pgp-expressing tumors, without adding significant extra-toxicities to doxorubicin treatment. Interestingly, Glab did not change the expression of Pgp, but it reduced the affinity for Pgp and the efflux of doxorubicin, as suggested by the increased Km and the reduced Vmax. In silico molecular docking predicted that Glab binds two residues (phenylalanine 322, glutamine 721) localized in the transmembrane domains of Pgp, facing the extracellular environment. Moreover, site-directed mutagenesis identified glycine 185 as a critical residue mediating the reduced catalytic efficacy of Pgp elicited by Glab. We propose Glab as an effective and safe compound able to reverse doxorubicin resistance mediated by Pgp in triple negative breast cancers, opening the way to a new combinatorial approach that may improve chemotherapy efficacy in the most refractory and aggressive breast cancer.

Ambivalent stereotypes link to peace, conflict, and inequality across 38 nations.

A cross-national study, 49 samples in 38 nations (n = 4,344), investigates whether national peace and conflict reflect ambivalent warmth and competence stereotypes: High-conflict societies (Pakistan) may need clearcut, unambivalent group images distinguishing friends from foes. Highly peaceful countries (Denmark) also may need less ambivalence because most groups occupy the shared national identity, with only a few outcasts. Finally, nations with intermediate conflict (United States) may need ambivalence to justify more complex intergroup-system stability. Using the Global Peace Index to measure conflict, a curvilinear (quadratic) relationship between ambivalence and conflict highlights how both extremely peaceful and extremely conflictual countries display lower stereotype ambivalence, whereas countries intermediate on peace-conflict present higher ambivalence. These data also replicated a linear inequality-ambivalence relationship.

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.

Assessment of titanium dioxide nanoparticles toxicity via oral exposure in mice: effect of dose and particle size.

Objective: The aim of the present work is to evaluate the toxicity of titanium dioxide nanoparticles (TiO2NPs) according to their doses and particle sizes. Materials and methods: The effect of five days oral administration of TiO2NPs (21 and 80 nm) with different doses (50, 250 and 500 mg/kg body weight) was assessed in mice via measurement of oxidative stress markers; glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and nitric oxide (NO), liver function indices; aspartate and alanine aminotransferases (AST and ALT), chromosomal aberrations and liver histopathological pattern. Results: The results revealed drastic alterations in all the measured parameters and showed positive correlation with the gradual dose increment. In addition, the smaller particle size of TiO2NPS (21 nm) had more adverse effect in all the selected biochemical parameters, genetic aberrations and histological investigations. Conclusions: Toxicity of TiO2NPs increases in a dose-dependent manner and vice versa with particles size. The evaluated biomarkers are good indicators for TiO2NPs toxicity. More detailed studies are required before the recommendation of TiO2NPS as food additives.

More room for microphase separation: An extended study on binary liquids confined in SBA-15 cylindrical pores.

The confinement of liquid mixtures in porous channels provides new insight into fluid ordering at the nanoscale. In this study, we address a phenomenon of microphase separation, which appears as a novel fascinating confinement effect for fully miscible binary liquids. We investigate the structure of tert-butanol-toluene mixtures confined in the straight and mono-dispersed cylindrical nanochannels of SBA-15 mesoporous silicates (D = 8.3 nm). Small angle neutron scattering experiments on samples with carefully designed isotopic compositions are performed to systematically vary the scattering length density of the different compounds and assess the radial concentration profile of the confined phases. The resulting modulation of the Bragg reflections of SBA-15 is compared with the predictions from different core-shell models, highlighting a molecular-scale phase-separated tubular structure with the tert-butanol forming a layer at the pore surface, surrounding a toluene-rich core. The present structural study suggests that the microphase separation phenomenon in confinement, which so far had only been reported for a smaller pore size (D = 3.65 nm) and a unique mixture composition, must be considered as a general phenomenon. It also highlights the strength of neutron scattering method with isotopic substitution, which is a unique experimental approach to reveal this phenomenon.

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Single-nucleotide polymorphism of Toll-like receptor 4 and interleukin-10 in response to interferon-based therapy in Egyptian chronic hepatitis C patients.

Egypt has the highest prevalence of hepatitis C virus (HCV) in the world. It has been suggested that not only the virus but also the interaction between the virus and the host immune system is important in determining the course of the infection and the response to interferon (IFN)-based therapy. While the adaptive immune system plays a critical role in HCV infection, the innate immune system has only been recognized recently. Toll-like receptors (TLRs) form the cornerstone of the innate immune response. Interleukin-10 (IL-10) is one of the upstream regulators of TLR4. A possible interplay between TLR4 and IL-10 has been suggested. The present study aimed to investigate the role of single-nucleotide polymorphisms (SNPs) in TLR4 and IL-10-1082 and the expression levels of these proteins in predicting the response to treatment in chronic HCV patients. A total of 83 chronic HCV-infected Egyptian patients treated with peg-IFN-α2b-ribavirin combination therapy and 40 healthy subjects were included in this study. SNPs in the TLR4 rs2149356 and IL-10-1082 genes and their serum levels were assessed. Within the responders group, T/T and A/A genotypes were the significantly most frequent genotypes of TLR4 and IL-10-1082, respectively. Moreover, a higher frequency of T/T and A/A was found to be associated with lower serum TLR4 and IL-10 levels in our responder patients. In addition, subjects with the T/T genotype in the healthy control group had a lower serum TLR4 level than those with other genotypes. We conclude that the SNPs TLR4 rs2149356-T/T and IL-10-1082-A/A may be important predictors for HCV therapy.

Titanium dioxide nanostructure-loaded Adriamycin surmounts resistance in breast cancer therapy: ABCA/P53/C-myc crosstalk.

Aim: To clarify the alternation of gene expression responsible for resistance of Adriamycin (ADR) in rats, in addition to investigation of a novel promising drug-delivery system using titanium dioxide nanoparticles loaded with ADR (TiO2-ADR). Method: Breast cancer was induced in female Sprague-Dawley rats, followed by treatment with ADR (5 mg/kg) or TiO2-ADR (2 mg/kg) for 1 month. Results: Significant improvements in both zinc and calcium levels were observed with TiO2-ADR treatment. Gene expression of ATP-binding cassette transporter membrane proteins (ABCA1 & ABCG1), P53 and Jak-2 showed a significant reduction and overexpression of the C-myc in breast cancer-induced rats. TiO2-ADR demonstrated a notable ability to upregulate these genes. Conclusion: TiO2-ADR could be a promising drug-delivery system for breast cancer therapy.

The current study aimed to investigate a novel and promising drug-delivery system to overcome the resistance problem by loading Adriamycin (ADR) into titanium dioxide nanoparticles (TiO₂). The study also aimed to clarify the changes in gene expression responsible for the development of ADR resistance, in a rat model. First, animals were divided into four groups of ten each. Breast cancer was induced in female Sprague-Dawley rats by administering two doses of DMBA (50 and 25 mg/kg), followed by treatment with ADR at a dose of 5 mg/kg for 1 month, or TiO₂-ADR at a dose of 2 mg/kg for 1 month. Biochemical and molecular analyses were conducted. Zinc and calcium levels were found to significantly decrease after cancer induction. Treatment with ADR alone or in combination with TiO₂ showed a significant improvement in both mineral levels, with the TiO₂-ADR group showing superior results. Gene expression of ATP-binding cassette transporter membrane proteins (ABCA1 & ABCG1), P53 and Jak-2 showed a significant decrease after DMBA-induced breast cancer. However, both the ADR- and TiO₂-ADR-treated groups showed a notable increase in gene expression, with the TiO₂-ADR group showing the highest increase. On the other hand, there was a significant overexpression of the C-myc gene after DMBA-induced breast cancer. However, both ADR and TiO₂-ADR treatments resulted in a notable decrease in C-myc gene expression. Based on the data, TiO₂-ADR could be a promising drug-delivery system for breast cancer therapy.

Collaboration of Hprt/K-RAS/c-Myc mutation in the oncogenesis of T-lymphocytic leukemia: a comparative study.

Aim: Leukemia is a malignant clonal illness stem from the mutations of hematopoietic cells. Acute lymphoblastic leukemia is one of the utmost prevalent kinds of leukemia, is brought on by atypical lymphoid progenitor cell division in the bone marrow. Materials & methods: A comparative study between, titanium Nanoparticle-loaded doxorubicin or cisplatin and lactoferrin-loaded doxorubicin or cisplatin, on 7,12-dimethylbenz[a]-anthracene (DMBA)-induced leukemia was investigated and confirming the hypothesis that messenger RNA of Hprt/K-RAS/c-Myc/SAT-2/P53/JAK-2 is a forthcoming signaling pathways in leukemia. Results: A significant alteration in Hprt, K-RAS, C-Myc, P53, JAK-2 and SAT-2 genes was observed post DMBA intoxication the aforementioned Nanodrugs modulated these signaling pathways. Conclusion: The carrier-loaded drugs triggered cytotoxicity of cancer cells via enhancing drug efficacy and bio-availability.

Leukemia is the abnormal growth of white blood cells that is responsible for fighting infection. Cisplatin and doxorubicin are commonly used anticancer drugs that can combat leukemic cells however they faced some problems of poor solubility and toxicity to normal cells. Thus we designed nanodrugs as Ti-NPs-cisplatin or DOX and lactoferrin-cisplatin or DOX and compared them with DOX and cisplatin and studied their impact on DMBA-induced leukemia in rat models. Monitoring apoptotic and cell survival genes was performed. Treatment with the nanodrugs could be promising in targeting cancer cells and improving drug bio-availability thus inducing cancer cell death.

Time-based investigation of urinary metabolic markers for Type 2 diabetes: Metabolomics approach for diabetes management.

Diabetes is considered one of the most important health emergencies worldwide and Egypt has 8.2 million diabetic patients according to the International Diabetes Federation report in 2017. The objective of this study was to monitor the time-course variation in the metabolic profile of diabetic rats to detect urinary metabolic biomarkers using the metabolomics approach. Type 2 diabetes was induced in male Wistar albino rats using a single intraperitoneal injection of 40 mg/kg of streptozotocin following oral administration of 10% fructose in drinking water for 3 weeks. Then, urine was collected for 24 h from rats at three time points (0, 2, and 4 weeks after confirmation of diabetes), and were analyzed by nuclear magnetic resonance (H1 -NMR), followed by multivariate data analysis. The results from H1 -NMR pointed out that d-glucose, taurine, l-carnitine, l-fucose, 1,5-anhydrosorbitol, and d-galactose levels showed consistent significant variation (p < 0.05) between the positive (diabetic) and negative (normal) controls during the whole experimental period. Also, with the disease progression, myoinositol, and l-phenylalanine levels were significantly altered (p < 0.05) after 2 weeks and this alteration was maintained till the end of the 4-week experimental period in the positive control group. From the results of the present study, it could be concluded that we cannot depend only on glucose levels for prognostic purposes since there are other metabolic disturbances in diabetes which need to be tracked for better disease prognosis.

Metabolomic profiling to reveal the therapeutic potency of Posidonia oceanica nanoparticles in diabetic rats.

Posidonia oceanica is a sea grass belonging to the family Posidoniaceae, which stands out as a substantial reservoir of bioactive compounds. In this study, the secondary metabolites of the P. oceanica rhizome were annotated using UPLC-HRESI-MS/MS, revealing 86 compounds including simple phenolic acids, flavonoids, and their sulphated conjugates. Moreover, the P. oceanica butanol extract exhibited substantial antioxidant and antidiabetic effects in vitro. Thus, a reliable, robust drug delivery system was developed through the encapsulation of P. oceanica extract in gelatin nanoparticles to protect active constituents, control their release and enhance their therapeutic activity. To confirm these achievements, untargeted GC-MS metabolomics analysis together with biochemical evaluation was employed to investigate the in vivo anti-diabetic potential of the P. oceanica nano-extract. The results of this study demonstrated that the P. oceanica gelatin nanoparticle formulation reduced the serum fasting blood glucose level significantly (p < 0.05) in addition to improving the insulin level, together with the elevation of glucose transporter 4 levels. Besides, multivariate/univariate analyses of the GC-MS metabolomic dataset revealed several dysregulated metabolites in diabetic rats, which were restored to normalized levels after treatment with the P. oceanica gelatin nanoparticle formulation. These metabolites mainly originate from the metabolism of amino acids, fatty acids and carbohydrates, indicating that this type of delivery was more effective than the plain extract in regulating these altered metabolic processes. Overall, this study provides novel insight for the potential of P. oceanica butanol extract encapsulated in gelatin nanoparticles as a promising and effective antidiabetic therapy.

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.

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.

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells.

Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest spectrum of substrates. Curcumin (CURC) is a Pgp inhibitor, but it is poorly soluble and bioavailable. To overcome these limitations, we validated the efficacy and safety of CURC, loaded in biocompatible solid lipid nanoparticles (SLNs), with or without chitosan coating, with the goal of increasing the stability, homogeneous water dispersibility, and cellular uptake. Both CURC-loaded SLNs were 5-10-fold more effective than free CURC in increasing the intracellular retention and toxicity of doxorubicin in Pgp-expressing triple negative breast cancer (TNBC). The effect was due to the decrease of intracellular reactive oxygen species, consequent inhibition of the Akt/IKKα-ß/NF-kB axis, and reduced transcriptional activation of the Pgp promoter by p65/p50 NF-kB. CURC-loaded SLNs also effectively rescued the sensitivity to doxorubicin against drug-resistant TNBC tumors, without signs of systemic toxicity. These results suggest that the combination therapy, based on CURC-loaded SLNs and doxorubicin, is an effective and safe approach to overcome the Pgp-mediated chemoresistance in TNBC.

Modified Stoppa as an alternative surgical approach for fixation of anterior fracture acetabulum: a randomized control clinical trial.

BACKGROUND: Fracture acetabulum is a challenging, difficult to treat orthopedic injury due to its location and associated concomitant injuries. The modified Stoppa approach for reduction of fracture acetabulum improves access to quadrilateral surface and posterior column and is considered to be advantageous in many facets of the surgery. METHODS: A randomized controlled clinical study was conducted to provide an update on our experience with modified Stoppa as a favorable surgical approach in acetabular fractures. In the period between 2015 and 2017; 18 patients with acetabular fractures operated by the classical ilioinguinal approach were retrospectively reviewed through their medical records as a controlled group and selected 20 patients with acetabular fractures were operated in the period between 2017 and 2019 using the modified Stoppa approach, as a clinical case group. The two groups were compared regarding operative data and postoperative clinical data, complications, and follow up. Cases were operated in Al Zahraa University Hospital and Nasr City Insurance Hospital by the same surgeon and one of the co-authors. RESULTS: (Group A) those operated by ilioinguinal approach and (Group B) those operated using Stoppa approach. The whole study included 25 males (66%); mean age was 41.8 ± 8.42 (range 18-65) years. The mean follow-up period was 18.5 months with 5 patients lost to follow-up. Both column fractures were observed in most of the patients (45%). We observed anatomical reduction, excellent clinical outcome scores in 75% of patients of group B (p = 0.030), and less complications. CONCLUSION: Our findings indicated that the modified Stoppa approach is the most convenient approach when surgery is required and achieved favorable results in the treatment of anterior acetabular fractures because it improves visualization in lateral compression injuries and allows treatment of both column fractures with single incision. Hence, it is recommended as an alternative to ilioinguinal approach in developing countries. Further, larger-scale comparative studies of the two surgical modalities for different acetabular fracture types and long-term complications are recommended. TRIAL REGISTRATION: A retrospective registration is proceeding through Clinicaltrials.gov. LEVEL OF EVIDENCE: Level III, therapeutic clinical study.

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.

Lipidomic analysis reveals the efficiency of Eclipta prostrata on diet-induced nonalcoholic fatty liver disease in rats.

Non-alcoholic fatty liver disease is a leading cause of chronic liver disease in western countries. The current study aimed to detect and evaluate lipidomic biomarkers for early detection of NAFLD as well as the potential efficiency of methanolic extract of Eclipta prostrata (E. prostrata) on disease management. In this study, Phytochemical screening of E. prostrata methanolic extract was performed using HPLC. NAFLD was induced in albino rats using a high-fat diet together with cholesterol and cholic acid. Comprehensive lipidomic analyses on sera from rats bearing NAFLD as well as normal healthy animals were carried out based on GCMS and multivariate data analysis. The results showed that high doses (300&200 mg/kg.BW) of E. prostrata extract exhibited significant improvement in liver enzymes (ALT & AST) and lipid profile [total cholesterol (TC), triacylglycerides (TAGs), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C)] in rats bearing NAFLD. Glycerol, linoleic acid, arachidonic acid and cholest-5-en-3-ol (3ß) acetate were detected as lipidomic biomarkers for early detection of NAFLD in rats' sera. Furthermore, E. prostrata extract showed a significant amelioration in the levels of these metabolic biomarkers in both protective and treated groups. These finding devoutly recommend using of lipidomic biomarkers for early detection of NAFLD and E. prostrata could be used as a protective agent as well as ameliorate this disease through its probable action on the fore-mentioned metabolites.

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.

Metabolomics approach for multibiomarkers determination to investigate dengue virus infection in human patients.

BACKGROUND: Dengue is one of the major public health problems in the world, affecting more than fifty million cases in tropical and subtropical region every year. The metabolome, as pathophysiological end-points, provide significant understanding of the mechanism and progression of dengue pathogenesis via changes in the metabolite profile of infected patients. Recent developments in diagnostic technologies provide metabolomics for the early detection of infectious diseases. METHODS: The mid-stream urine was collected from 96 patients diagnosed with dengue fever at Penang General Hospital (PGH) and 50 healthy volunteers. Urine samples were analyzed with proton nuclear magnetic resonance (1H NMR) spectroscopy, followed by chemometric multivariate analysis. NMR signals highlighted in the orthogonal partial least square-discriminant analysis (OPLS-DA) S-plots were selected and identified using Human Metabolome Database (HMDB) and Chenomx Profiler. A highly predictive model was constructed from urine profile of dengue infected patients versus healthy individuals with the total R2Y (cum) value 0.935, and the total Q2Y (cum) value 0.832. RESULTS: Data showed that dengue infection is related to amino acid metabolism, tricarboxylic acid intermediates cycle and ß-oxidation of fatty acids. Distinct variations in certain metabolites were recorded in infected patients including amino acids, various organic acids, betaine, valerylglycine, myo-inositol and glycine. CONCLUSION: Metabolomics approach provides essential insight into host metabolic disturbances following dengue infection.