Cerium and Yttrium Oxide Nanoparticles and Nano-selenium Produce Protective Effects Against H2O2-induced Oxidative Stress in Pancreatic Beta Cells by Modulating Mitochondrial Dysfunction.

BACKGROUND: Type 1 diabetes mellitus is characterized by the destruction of insulin- producing Beta cells in the pancreas. Researchers hope that islet transplantation will help to patients with insulin-dependent diabetes mellitus (IDDM). Oxidative stress is the most important challenge that beta cells face to it after isolation, and mitochondrial dysfunction is a crucial mediator in beta cells death. Hence, therapeutic approaches can shift to antioxidants through the application of nanoparticles such as cerium and yttrium oxide nanoparticles (Cer and Ytt Ox NPs) and nano-selenium (Nan Se). OBJECTIVE: This study evaluates the effects of Cer and Ytt Ox NPs and Nan Se on H2O2- induced oxidative stress in pancreatic beta cells with focus on mitochondrial dysfunction pathway. METHODS: CRI-D2 beta-cell line were pretreated with Cer Ox NPs (200 µM) + Ytt Ox NPs (0.5 µg/mL) for 3 days and/or Nan Se (0.01 µM) for 1 day. Then markers of oxidative stress, mitochondrial dysfunction, insulin and glucagon secretion were measured. RESULTS: We reported a decrease in H2O2-induced reactive oxygen species (ROS) level and glucagon secretion, and an increase in H2O2-reduced ATP/ADP ratio, MMP, as well as UCP2 protein expression, and insulin secretion by pretreatment of CRI-D2 cells with Cer and Ytt Ox NPs and/or Nan Se. CONCLUSION: We found maximum protective effect with Cer and Ytt Ox NPs on CRI-D2 beta-cell line exposed by H2O2 for keeping beta cells alive until transplant whereas combination of Cer and Ytt Ox NPs and Nan Se had very little protective effect in this condition.

An Adaptive Robust Control Strategy in a Cancer Tumor-Immune System under Uncertainties.

We propose an adaptive robust control for a second order nonlinear model of the interaction between cancer and immune cells of the body to control the growth of cancer and maintain the number of immune cells in an appropriate level. Most of the control approaches are based on minimizing the drug dosage based on an optimal control structure. However, in many cases, measuring the exact quantity of the model parameters is not possible. This is due to limitation in measuring devices, variational and undetermined characteristics of micro-environmental factors. It is of great importance to present a control strategy that can deal with these unknown factors in a nonlinear model.

Antioxidant and Anticancer Activities of Walnut (Juglans regia L.) Protein Hydrolysates Using Different Proteases.

Walnut (Juglans regia L.) contains approximately 20-25 % protein with abundant essential amino acids. The enzymatic hydrolysate of Persian walnut (Chandler) seed proteins was prepared by incubation with three different proteases, including pancreatic chymotrypsin and trypsin, and a microbial enzyme proteinase K. The hydrolysates were found to possess excellent antioxidant capacities. The peptide fractions scavenged the 2, 2'-anizo-bis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) free radicals and inhibited the activity of reactive oxygen species. Walnut protein hydrolysates were also tested, for the first time, against the viability of human breast (MDA-MB231) and colon (HT-29) cancer cell lines. MTT, [3-(4, 5dimethylthiazolyl)-2,5-diphenyl-tetrazolium bromide], assay was used to assess in vitro cancer cell viability upon treatment with the peptide fractions. The peptide fractions showed cell growth inhibition of 63 ± 1.73 % for breast cancer and 51 ± 1.45 % for colon cancer cells. Thus, a direct correlation between antioxidant and anticancer activities of walnut peptide fractions exists and supports their potential therapeutic benefit.

Involvement of p-CREB and phase II detoxifying enzyme system in neuroprotection mediated by the flavonoid calycopterin isolated from Dracocephalum kotschyi.

PURPOSE: There is an increasing amount of experimental evidence that oxidative stress has a central role in the neuropathology of neurodegenerative diseases. It has been suggested that the loss of cell function results from the increased oxidative damage to proteins and DNA. Herein, we investigated the effect of a natural neuroprotective flavonoid, calycopterin, on H2O2-induced disruption of phase II detoxifying enzyme system and cAMP response element binding protein (CREB) phosphorylation. METHODS: PC12 cells were treated with 25, 50 and 100 µM of calycopterin for 3h, followed by adding H2O2 (150 µM) for 24 h. The extent of apoptosis was assessed by comet assay. The level of phosphorylated CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), glutamylcysteine synthetase (γ-GCS) and heme oxygenase 1 (HO-1) were measured by western blot method. The concentration of glutathione (GSH) was determined in whole cell lysate using dithionitrobenzoic acid method. Superoxide dismutase (SOD) activity was measured by colorimetric assay. RESULT: Morphological analysis of protection induced by calycopterin, determined by comet assay, showed that calycopterin reduced DNA in tail. We found that H2O2 decreased mitochondrial membrane potential (MMP), while, calycopterin prevented this decrease in MMP in presence of H2O2. In H2O2-treated cells, calycopterin also suppressed cytochrome C release to cytosol that is necessary for maintaining mitochondrial homeostasis in survived cells. Moreover, calycopterin, in presence of H2O2 inhibited the decrease caused by oxidative stress in stress-sensing transcription factors, CREB and Nrf2, which play an important role in antioxidant capacity of the cell. There was also an increase in γ-GCS and HO-1 levels in calycopterin pretreated cells. In the presence of H2O2, calycopterin inhibited decrease in GSH level and SOD activity. CONCLUSION: We provided documentation of neuroprotective effect of a natural flavone, calycopterin, against H2O2-induced oxidative stress in differentiated PC12 cells by modulating the level of CREB phosphorylation and Nrf2 pathway.

Calycopterin promotes survival and outgrowth of neuron-like PC12 cells by attenuation of oxidative- and ER-stress-induced apoptosis along with inflammatory response.

There is mounting evidence implicating the role of oxidative stress induced by reactive oxygen species (ROS) in neurodegenerative disease, including Alzheimer's disease. Herein we investigated the neuroprotective potential of a natural flavonoid, calycopterin, against H(2)O(2)-induced cell death in differentiated PC12 cells. We pretreated PC12 cells with 25, 50, and 100 µM calycopterin followed by the addition of H(2)O(2) as an oxidative stress agent. We measured cell viability by the MTT test and found that 50 µM is the best protective concentration of calycopterin. Moreover, we measured six different parameters of neurite outgrowth. Interestingly, we found that calycopterin not only protects PC12 cells against H(2)O(2)-induced apoptosis but also defends against the destructive effect of oxidative stress on the criteria of neural differentiation. Calycopterin decreased ER stress-associated proteins including calpain and caspase-12, and suppressed ERK, JNK, and p38 MAPK phosphorylation. Moreover, calycopterin inhibited H(2)O(2)-induced nuclear translocation of nuclear factor-κB, a known regulator of a host of genes involved in specific stress and inflammatory responses. This observation was perfectly in agreement with the decrease of COX-2 and TNF-α levels. Calycopterin reduced intracellular ROS levels and increased catalase activity. The protective effect of this compound could represent a promising approach for the treatment of neurodegenerative diseases.

Neuroprotective effect of Salvia sahendica is mediated by restoration of mitochondrial function and inhibition of endoplasmic reticulum stress.

Herein, we investigated the protective effect of Salvia sahendica against H(2)O(2)-induced cell death in rat pheochromocytoma (PC12) cells. Our data show that S. sahendica blocks apoptosis pathway by inhibition of cytochrome c release from mitochondria and leakage of calcium from endoplasmic reticulum. It also activates/inactivates two members of Bcl-2 family, Bax and Bcl-2. Bax inhibition and Bcl-2 activation suppress release of cytochrome c from mitochondria that prevents cleavage of caspase-3. Besides S. sahendica suppresses ER stress via attenuation of intracellular levels of calcium. Suppression of ER stress decreased calpain activation and subsequently cleavage of caspase-12. Altogether, these results indicate that S. sahendica protects PC12 cells treated with H(2)O(2) via suppression of upstream factors of apoptosis pathway. While oxidative stress is an early event in Alzheimer disease, it seems that S. sahendica prevents deleterious effects of reactive oxygen species by stabilizing mitochondrial membranes and inhibiting ER stress.