Mulberry Fruit Extract Ameliorates Nonalcoholic Fatty Liver Disease (NAFLD) through Inhibition of Mitochondrial Oxidative Stress in Rats.

Mulberry is known to have pharmacological effects against cholesterol, obesity, and dyslipidemia. Many studies have revealed that mulberry leaf possesses hepatoprotective properties against nonalcoholic fatty liver disease (NAFLD); however, mulberry fruit is less studied in this context. Therefore, this study aimed to investigate the preventive effects of mulberry fruit against high fat diet- (HFD-) induced NAFLD. To evaluate the effects of mulberry fruit on NAFLD, two doses of mulberry fruit ethanol extracts [MB, 100, and 200 mg/kg BW (body weight)] were given to HFD-fed rats for 10 weeks. MB dramatically prevented liver damage as shown by biochemical analysis of the liver injury markers, alanine transaminase, and aspartate transaminase. MB treatment significantly inhibited the increased levels of total cholesterol, triacylglycerol, and low-density lipoprotein-cholesterol but restored the level of high-density lipoprotein-cholesterol in HFD-fed rats. Notably, histological analysis of liver tissues demonstrated that MB substantially ameliorated lipid accumulation. Expression of cholesterol-regulating genes was also suppressed by MB treatment. For its underlying mechanisms, MB suppressed hepatic reactive oxygen species (ROS) overproduction and mitochondrial oxidative stress in HFD-fed rats. MB potentially protects liver tissue against NAFLD by inhibition of mitochondrial oxidative stress, suggesting its possible use as a therapeutic agent for treatment of NAFLD.

Cytotoxicity of lipid-soluble ginseng extracts is attenuated by plasma membrane redox enzyme NQO1 through maintaining redox homeostasis and delaying apoptosis in human neuroblastoma cells.

Lipid-soluble ginseng extracts (LSGE) is known to inhibit many types of cancer cells through arresting cell cycle and inducing apoptosis. Usually, normal cells are can also be damaged by anti-tumor reagents. The plasma membrane redox system (PMRS) is enhanced to compensate mitochondrial dysfunction and impaired energy metabolism. NADH-quinone oxidoreductase 1 (NQO1), a plasma membrane redox enzyme, is known to be induced by panaxytriol, one of components of lipid-soluble ginseng extracts (LSGE). The objective of this study was determine the mechanisms of NQO1 involved in neuroprotection in response to cytotoxicity induced by LSGE. Exposure of control SH-SY5Y cells to LSGE resulted in dramatic loss of cell viability in a dose-dependent manner. The loss of cell viability was significantly recovered in cells transfected with NQO1. LSGE-induced cell death occurred through apoptosis such as cell shrinkage, chromatin condensation and cleavage of poly (ADP-ribose) polymerase. These apoptotic features were significantly attenuated by overexpression of NQO1. Levels of oxidative/nitrative damage were highly elevated by LSGE in a dose-dependent manner. However, these elevated levels were greatly reduced by overexpression of NQO1. In addition, overexpression of NQO1 attenuated the decrease in mitochondrial complex I activity caused by LSGE. Taken together, these findings suggest that overexpressed NQO1 can protect cells against LSGE-induced cytotoxicity through lowering oxidative/nitrative damage and delaying apoptosis, supporting that stimulation of NQO1 activity could be a therapeutic targets in neurodegeration.

In situ diselenide-crosslinked polymeric micelles for ROS-mediated anticancer drug delivery.

Stimuli-responsive micelles have emerged as the drug carrier for cancer therapy since they can exclusively release the drug via their structural changes in response to the specific stimuli of the target site. Herein, we developed the in situ diselenide-crosslinked micelles (DCMs), which are responsive to the abnormal ROS levels of tumoral region, as anticancer drug carriers. The DCMs were spontaneously derived from selenol-bearing triblock copolymers consisting of polyethylene glycol (PEG) and polypeptide derivatives. During micelle formation, doxorubicine (DOX) was effectively encapsulated in the hydrophobic core, and diselenide crosslinks were formed in the shell. The DCMs maintained their structural integrity, at least for 6 days in physiological conditions, even in the presence of destabilizing agents. However, ROS-rich conditions triggered rapid release of DOX from the DOX-encapsulating DCMs (DOX-DCMs) because the hydrophobic diselenide bond was cleaved into hydrophilic selenic acid derivatives. Interestingly, after their systemic administration into the tumor-bearing mice, DOX-DCMs delivered significantly more drug to tumors (1.69-fold and 3.73-fold higher amount compared with their non-crosslinked counterparts and free drug, respectively) and effectively suppressed tumor growth. Overall, our data indicate that DCMs have great potential as drug carriers for anticancer therapy.

Phytochemicals in Ischemic Stroke.

Stroke is the second foremost cause of mortality worldwide and a major cause of long-term disability. Due to changes in lifestyle and an aging population, the incidence of stroke continues to increase and stroke mortality predicted to exceed 12 % by the year 2030. However, the development of pharmacological treatments for stroke has failed to progress much in over 20 years since the introduction of the thrombolytic drug, recombinant tissue plasminogen activator. These alarming circumstances caused many research groups to search for alternative treatments in the form of neuroprotectants. Here, we consider the potential use of phytochemicals in the treatment of stroke. Their historical use in traditional medicine and their excellent safety profile make phytochemicals attractive for the development of therapeutics in human diseases. Emerging findings suggest that some phytochemicals have the ability to target multiple pathophysiological processes involved in stroke including oxidative stress, inflammation and apoptotic cell death. Furthermore, epidemiological studies suggest that the consumption of plant sources rich in phytochemicals may reduce stroke risk, and so reinforce the possibility of developing preventative or neuroprotectant therapies for stroke. In this review, we describe results of preclinical studies that demonstrate beneficial effects of phytochemicals in experimental models relevant to stroke pathogenesis, and we consider their possible mechanisms of action.

Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.

UNLABELLED: Liver fibrosis is a common outcome of chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. No US Food and Drug Administration-approved targeted antifibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAILPEG ) that has a much longer half-life in rodents than native-type TRAIL. In this study, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. CONCLUSION: TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. (Hepatology 2016;64:209-223).

Cancer therapy using ultrahigh hydrophobic drug-loaded graphene derivatives.

This study aimed to demonstrate that curcumin (Cur)-containing graphene composites have high anticancer activity. Specifically, graphene-derivatives were used as nanovectors for the delivery of the hydrophobic anticancer drug Cur based on pH dependence. Different Cur-graphene composites were prepared based on polar interactions between Cur and the number of oxygen-containing functional groups of respective starting materials. The degree of drug-loading was found to be increased by increasing the number of oxygen-containing functional groups in graphene-derivatives. We demonstrated a synergistic effect of Cur-graphene composites on cancer cell death (HCT 116) both in vitro and in vivo. As-prepared graphene quantum dot (GQD)-Cur composites contained the highest amount of Cur nano-particles and exhibited the best anticancer activity compared to the other composites including Cur alone at the same dose. This is the first example of synergistic chemotherapy using GQD-Cur composites simultaneous with superficial bioprobes for tumor imaging.

Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system.

During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for the latter mechanism is grounded in the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examplesof such pathways include those involving the transcription factors nuclear factor erythroid 2-related factor 2, nuclear factor-κB, hypoxia-inducible factor 1α, peroxisome proliferator-activated receptor γ, and forkhead box subgroup O, as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against tissue injury and disease. Because neurons are particularly sensitive to potentially noxious phytochemicals, we focus on the nervous system but also include findings from other cell types in which actions of phytochemicals on specific signal transduction pathways have been more thoroughly studied.

Genistein mediates the anti-adipogenic actions of Sophora japonica L. extracts.

Previous studies showed that feeding diets containing the mature fruits of Sophora japonica L. prevented body weight gain and reduced fat mass in high-fat diet-induced obese mice. This observation has led to the hypothesis that extracts from S. japonica L. may inhibit adipocyte differentiation of preadipocytes. To elucidate the possible mechanisms for the anti-obesity action of S. japonica L., its effects on adipocyte differentiation were investigated in C3H10T1/2 mesenchymal stem cells and 3T3-L1 preadipocyte cells. The mature fruit of S. japonica L. was partitioned with ethanol, hexane, dichloromethane, ethyl acetate (EtOAc), and butanol to identify the active fractions. The EtOAc fraction extracts inhibited morphological differentiation and lipid accumulation in the C3H10T1/2 and 3T3-L1 preadipocytes. Molecular studies indicated that the EtOAc fraction extracts also reduced the expression of peroxisome proliferator-activated receptor γ and other adipocyte markers. Furthermore, among the fractions, the EtOAc fraction extracts had the highest total phenolic contents, suggesting that the polyphenols in the EtOAc fractions mediated the anti-adipogenic effects. Finally, high-performance liquid chromatography identified genistein, a known anti-adipogenic compound, as the probable mediator of the anti-adipogenic effects of the EtOAc fractions. This work validates the beneficial roles of S. japonica L. in controlling body weight and obesity-related metabolic diseases.

Selenium attenuates A beta production and A beta-induced neuronal death.

The objective of the present study was to examine the role of selenium in the metabolism of A beta and in A beta-induced neuronal death. Selenium treatment significantly reduced A beta 40, A beta 42, and sAPP beta production by reducing A beta producing beta-secretase and gamma-secretase activities. The lipid peroxidation product 4-Hydroxynonenal (HNE)-induced transcription of beta-secretase (BACE1) was blocked by selenium. Finally, our data show that selenium protects against HNE and A beta-mediated toxicity in primary cultured neurons. The present study suggests that selenium may be able to salvage the neuronal degeneration of Alzheimer's disease, thereby limiting beta-amyloid production and neuronal death.