Bone marrow stem cell-derived ß-cells: New issue for diabetes cell therapy.

This investigation aimed to establish the promising role of insulin-producing cells (IPCs) growing from bone marrow-mesenchymal stem cells (BM-MSCs) in relieving hyperglycemia induced in rats. BM-MSCs were differentiated into IPCs using three different protocols. The efficiency of BM-MSCs differentiation into IPCs in vitro was confirmed by detecting IPCs specific gene expression (Foxa-2, PDX-1 and Ngn-3) and insulin release assay. The in vivo study design included 3 groups of male Wistar rats; negative control group, diabetic group and IPCs-transfused group (5 ×106 cells of the most functional IPCs/rat). One month after IPCs infusion, serum glucose, insulin, c-peptide and visfatin levels as well as pancreatic glucagon level were quantified. Gene expression analysis of pancreatic Foxa-2 and Sox-17, IGF-1 and FGF-10 was done. Additionally, histological investigation of pancreatic tissue sections was performed. Our data clarified that, the most functional IPCs are those generated from BM-MSCs using differentiation protocol 3 as indicated by the significant up-regulation of Foxa-2, PDX-1 and Ngn-3 gene expression levels. These findings were further emphasized by releasing of a significant amount of insulin in response to glucose load. The transplantation of the IPCs in diabetic rats elicited significant decline in serum glucose, visfatin and pancreatic glucagon levels along with significant rise in serum insulin and c-peptide levels. Moreover, it triggered significant up-regulation in the expression levels of pancreatic Foxa-2, Sox-17, IGF-1 and FGF-10 genes versus the untreated diabetic counterpart. The histopathological examination of pancreatic tissue almost assisted the biochemical and molecular genetic analyses. These results disclose that the cell therapy holds potential to develop a new cure for DM based on the capability of BM-MSCs to generate ß-cell phenotype using specific protocol.

Unravelling the anti-inflammatory and antioxidant effects of standardized green and black caffeinated coffee, tea, and their mixtures in an obese male rat model: Insights from biochemical, metabolomic, and histopathological analyses.

Obesity is one of the major metabolic syndrome risk factors upon which altered metabolic pathways follow. This study aimed to discern altered metabolic pathways associated with obesity and to pinpoint metabolite biomarkers in serum of obese rats fed on high fructose diet using metabolomics. Further, the effect of standardized green versus black caffeinated aqueous extracts (tea and coffee) in controlling obesity and its comorbidities through monitoring relevant serum biomarkers viz. Leptin, adiponectin, spexin, malondialdehyde, total antioxidant capacity. Liver tissue oxidative stress (catalase, super oxide dismutase and glutathione) and inflammation (IL-1ß and IL-6) markers were assessed for green coffee and its mixture with green tea. Results revealed improvement of all parameters upon treatments with more prominence for those treated with green caffeinated extract (coffee and tea) especially in mixture. Upon comparing with obese rat group, the green mixture of coffee and tea exhibited anti-hyperlipidemic action through lowering serum triglycerides by 35.0% and elevating high density lipoprotein by 71.0%. Black tea was likewise effective in lowering serum cholesterol and low density lipoprotein by 28.0 and 50.6%, respectively. GC-MS- based metabolomics of rat serum led to the identification of 34 metabolites with obese rat serum enriched in fatty acids (oleamide).

An ellagitannin-loaded CS-PEG decorated PLGA nano-prototype promotes cell cycle arrest in colorectal cancer cells.

Colorectal cancer is associated with significant morbidity and mortality worldwide. Egypt, as a developing country, has a high-rise incidence of cancer. The current study objective was to investigate the antitumor influences of ellagitannin-loaded CS-PEG-decorated PLGA nano-prototypes against human colorectal cancer cell lines (HCT 116 as well as Caco-2) in vitro. Doxorubicin (DOX), punicalin (PN), and punicalagin (PNG)-encapsulated chitosan-polyethylene glycol-decorated PLGA (PLGA-CS-PEG) nanoparticles (NPs) were described. The cytotoxicity of each preparation was evaluated using MTT assays in HCT 116 as well as Caco-2 cells during G0, G1, S, and G2 cell cycle phases. Cell cycle-related gene expression and protein levels were measured after treatment. Reactive oxygen species (ROS) levels were also measured. Both PN and PNG PLGA-CS-PEG NPs induce colon cancer cell death with cell cycle arrest in the G1 phase in vitro. Caco-2 cells were more sensitive to the nano-therapy than HCT 116 cells. Upon treatment, the ratio of Bax to Bcl-2 expression was increased following nano-therapy, with increased levels of Cas-3 and decreased expression of Bcl-2, PI3k, and NF-ĸB compared to control. The nitric oxide level (NO), a marker of ROS, was increased following nano-therapy compared to control. In conclusion, ROS-mediated cell cycle arrest can be induced by PN as well as PNG nano-therapy in cell lines of colorectal cancer.

Nanotherapy: New Approach for Impeding Hepatic Cancer Microenvironment via Targeting Multiple Molecular Pathways.

OBJECTIVE: Hepatocellular carcinoma (HCC) microenvironment has been recognized as a key contributor for cancer progression, metastasis, and drug resistance. The crosstalk between tumor cells, the vascular endothelial growth factor (VEGF), and the chemokine (C-C motif) ligand 2 (CCL2) signaling networks mediates immunoinhibitory impact and facilitates tumor angiogenesis. The current investigation aimed at exploring the potent anti-cancer activity of the newly designed nano-based anti-cancer therapy comprising anti-VEGF drug, avastin (AV), and CCR2 antagonist (CR) to counteract HCC and tracking its mode of action in vivo. METHODS: The prepared AV, CR, and AVCR nanoprototypes were characterized by nanoscale characterization techniques in our previous work. Here, they are applied for unearthing their anti-cancer properties / mechanisms in hepatic cancer-induced rats via analyzing protein levels and genetic expression of the elements incorporated in the angiogenesis, apoptosis, and metastasis signalling pathways. RESULTS: The present results revealed a significant down-regulation in the angiogenesis, survival and metastasis indices along with up-regulation in the pro-apoptotic mediators upon treatment of hepatic cancer-bearing rats with the novel synthesized nanomaterials when compared with the untreated counterparts. We showed across HCC model that anti-VEGF in combination with CCR2 antagonism therapy leads to sensitization and enhanced tumor response over anti-VEGF or CCR2 antagonism monotherapy, particularly in its nanoscale formulation. CONCLUSION: The present approach provides new mechanistic insights into the powerful anti-hepatic cancer advantage of the novel nanoprototypes which is correlated with modulating critical signal transduction pathways implicated in tumor microenviroment such as angiogenesis, apoptosis and metastasis. This research work presents a substantial foundation for future studies focused on prohibiting cancer progression and recovery by targeting tumor microenviroment.

Newly Synthesized Punicalin and Punicalagin Nano-Prototypes Induce Breast Cancer Cytotoxicity Through ROS-Mediated Apoptosis.

OBJECTIVE: Globally, breast cancer represents serious cause of morbidity and mortality. Our goal is to improve nutraceuticals that have the ability to overlap the side effects of conventional therapies and promising tumoricidal effects by using nanotechnology techniques. The current work was premeditated to explore the apoptotic effects of punicalin (PN) and punicalagin (PNG) nano-prototypes, derived from Punica granatum, on human breast cancerous MCF7 and MDA-MB-231 cells in vitro. METHODS: Firstly, we prepared and characterized of PN, PGN, and 5-flurouracil (FU)-loaded PLGA, PLGA-coated-CS, and PLGA-coated-CS-PEG nano-prototypes. Then, we studied the toxicological and biochemical effects of all nanoformulations. Finally, we measured the genetic and protein expression levels of apoptotic and survival candidates in cancer cells. RESULTS: Our results showed that the newly synthesized nano-prototypes had cytotoxic and apoptotic effects on MCF7 and MDA-MB-231 cell lines. Moreover, they up-regulated Bax and Cas-3 expression levels, as well as down-regulated BCL-2, NF-ĸB and PI3k expression levels compared to control. Nitric oxide (NO) and zinc (Zn) levels were significantly elevated (P < 0.05) after the application of PN and PNG nano-prototypes compared to the control. CONCLUSION: PN and PNG nano-prototypes of PLGA decorated with CS and PEG enhanced the anti-cancer activity through induction of cytotoxicity, reactive oxygen species (ROS)-mediated apoptosis.

Phytochemical Analysis and Anti-cancer Investigation of Boswellia serrata Bioactive Constituents In Vitro.

Cancer is a major health obstacle around the world, with hepatocellular carcinoma (HCC) and colorectal cancer (CRC) as major causes of morbidity and mortality. Nowadays, there isgrowing interest in the therapeutic use of natural products for HCC and CRC, owing to the anticancer activity of their bioactive constituents. Boswellia serrata oleo gum resin has long been used in Ayurvedic and traditional Chinese medicine to alleviate a variety of health problems such as inflammatory and arthritic diseases. The current study aimed to identify and explore the in vitro anticancer effect of B. Serrata bioactive constituents on HepG2 and HCT 116 cell lines. Phytochemical analysis of volatile oils of B. Serrata oleo gum resin was carried out using gas chromatography- mass spectrometry (GC/MS). Oleo-gum-resin of B. Serrata was then successively extracted with petroleum ether (extract 1) and methanol (extract 2). Gas-liquid chromatography (GLC) analysis of the lipoidal matter was also performed. In addition, a methanol extract of B. Serrata oleo gum resin was phytochemically studied using column chromatography (CC) and thin layer chromatography (TLC) to obtain four fractions (I, II, III and IV). Sephadex columns were used to isolate ß-boswellic acid and identification of the pure compound was done using UV, mass spectra, 1H NMR and 13C NMR analysis. Total extracts, fractions and volatile oils of B. Serrata oleo-gum resin were subsequently applied to HCC cells (HepG2 cell line) and CRC cells (HCT 116 cell line) to assess their cytotoxic effects. GLC analysis of the lipoidal matter resulted in identification of tricosane (75.32%) as a major compound with the presence of cholesterol, stigmasterol and ß-sitosterol. Twenty two fatty acids were identified of which saturated fatty acids represented 25.6% and unsaturated fatty acids 74.4% of the total saponifiable fraction. GC/MS analysis of three chromatographic fractions (I,II and III) of B. Serrata oleo gum resin revealed the presence of pent-2-ene-1,4-dione, 2-methyl- levulinic acid methyl ester, 3,5- dimethyl- 1- hexane, methyl-1-methylpentadecanoate, 1,1- dimethoxy cyclohexane, 1-methoxy-4-(1-propenyl)benzene and 17a-hydroxy-17a-cyano, preg-4-en-3-one. GC/MS analysis of volatile oils of B. Serrata oleo gum resin revealed the presence of sabinene (19.11%), terpinen-4-ol (14.64%) and terpinyl acetate (13.01%) as major constituents. The anti-cancer effect of two extracts (1 and 2) and four fractions (I, II, III and IV) as well as volatile oils of B. Serrata oleo gum resin on HepG2 and HCT 116 cell lines was investigated using SRB assay. Regarding HepG2 cell line, extracts 1 and 2 elicited the most pronounced cytotoxic activity with IC50 values equal 1.58 and 5.82 µg/mL at 48 h, respectively which were comparable to doxorubicin with an IC50 equal 4.68 µg/mL at 48 h. With respect to HCT 116 cells, extracts 1 and 2 exhibited the most obvious cytotoxic effect; with IC50 values equal 0.12 and 6.59 µg/mL at 48 h, respectively which were comparable to 5-fluorouracil with an IC50 equal 3.43 µg/ mL at 48 h. In conclusion, total extracts, fractions and volatile oils of B. Serrata oleo gum resin proved their usefulness as cytotoxic mediators against HepG2 and HCT 116 cell lines with different potentiality (extracts > fractions > volatile oil). In the two studied cell lines the cytotoxic acivity of each of extract 1 and 2 was comparable to doxorubicin and 5-fluorouracil, respectively. Extensive in vivo research is warranted to explore the precise molecular mechanisms of these bioactive natural products in cytotoxicity against HCC and CRC cells.

Significance of Rumex vesicarius as anticancer remedy against hepatocellular carcinoma: a proposal-based on experimental animal studies.

Rumex vesicarius is an edible herb distributed in Egypt and Saudi Arabia. The whole plant has significant value in folk medicine and it has been used to alleviate several diseases. Hepatocellular carcinoma (HCC), the major primary malignant tumor of the liver, is one of the most life-threatening human cancers. The goal of the current study was to explore the potent role of Rumex vesicarius extract against HCC induced in rats. Thirty adult male albino rats were divided into 3 groups: (I): Healthy animals received orally 0.9% normal saline and served as negative control group, (II): HCC group in which rats were orally administered N-nitrosodiethylamine NDEA, (III): HCC group treated orally with R. vesicarius extract in a dose of 400 mg/kg b.wt daily for two months. ALT and AST, ALP and γ-GT activities were estimated. CEA, AFP, AFU, GPC-3, Gp-73 and VEGF levels were quantified. Histopathological examination of liver tissue sections was also carried out. The results of the current study showed that the treatment of the HCC group with R. vesicarius extract reversed the significant increase in liver enzymes activity, CEA, AFP, AFU, glypican 3, golgi 73 and VEGF levels in serum as compared to HCC-untreated counterparts. In addition, the favorable impact of R. vesicarius treatment was evidenced by the marked improvement in the histopathological features of the liver of the treated group. In conclusion, the present experimental setting provided evidence for the significance of R. vesicarius as anticancer candidate with a promising anticancer potential against HCC. The powerful hepatoprotective properties, the potent antiangiogenic activity and the effective antiproliferative capacity are responsible for the anticancer effect of this plant.

Possible therapeutic uses of Salvia triloba and Piper nigrum in Alzheimer's disease-induced rats.

This study aimed to investigate the role of Salvia triloba L. and Piper nigrum extracts in ameliorating neuroinflammatory insults characteristic of Alzheimer's disease (AD) in an experimentally induced rat model. Adult male Sprague-Dawley rats were classified into Group 1 (n=10): normal healthy animals serving as the negative control group; Group 2 (n=60): the AD-induced group. After AD induction, animals in the AD-induced group were divided randomly and equally into 6 subgroups. The first subgroup served as AD control; the second one, which served as positive control, was treated orally with the conventional therapy for AD (rivastigmine) at a dose of 0.3 mg/kg body weight (b.w.) daily for 3 months. The third and fourth subgroups were, respectively, treated orally with the S. triloba extract at a dose of 750 and 375 mg/kg b.w. daily for 3 months. The fifth and sixth subgroups were, respectively, treated orally with the P. nigrum extract at a dose of 187.5 and 93.75 mg/kg b.w. daily for 3 months. Levels of brain acetylcholine (Ach), serum and brain acetylcholinesterase (AchE) activity, C-reactive protein (CRP), total nuclear factor kappa-B (NF-κB), and monocyte chemoattractant protein-1 (MCP-1) were estimated. The results showed that administration of AlCl3 resulted in a significant elevation in the levels of AchE activity, CRP, NF-κB, and MCP-1 accompanied with a significant depletion in the Ach level. Treatment of AD rats with each of the selected medicinal plant extracts caused marked improvement in the measured biochemical parameters. In conclusion, S. triloba and P. nigrum methanolic extracts have potent anti-inflammatory effects against neuroinflammation characterizing AD.