Cognitive impairment in diabetes mellitus and its management by transcription factor Nrf2-mediated antioxidant defense system

Diabetes mellitus has been an epidemic in the twenty-first century and an approximately 50% risk of diabetes predisposed to cognitive decline leading to dementia in humans. There is an urgent need to understand the pathophysiology and identify molecular targets of cognitive impairment in diabetes mellitus that might lead to improved therapy. Mounting evidence indicates that nuclear factor erythroid 2-related factor 2 (Nrf2) and its regulated downstream antioxidant genes are emerging therapeutic targets. In this chapter, we introduce cognitive dysfunction in diabetes mellitus and its hallmarks, particularly its pathological mechanisms related to oxidative stress in the brain, then justify the role of the transcription factor Nrf2-mediated antioxidant defense system in attenuating cognitive decline in diabetes mellitus. Studies on Nrf2 inducers sourced from natural products (i.e., sulforaphane, astaxanthin, resveratrol, quercetin) that have shown potent cognitive improvement in diabetic models are discussed. These studies have demonstrated that Nrf2 inducers drive the antioxidant and anti-inflammatory responses in the hippocampus region and effectively improve the spatial and memory function in diabetic rats/mice. However, evidence from large and well-designed clinical trials is warranted to support Nrf2 inducers as promising therapeutic agents in the management of cognitive impairment in diabetes mellitus

Synergistic protective effect of curcumin and resveratrol against oxidative stress in endothelial EAhy926 cells

Curcumin (C) and resveratrol (R) are two well-known nutraceuticals with strong antioxidant activity that can protect cells from oxidative stress. This study aims to investigate the synergy of CR combinations in protecting human endothelial EAhy926 cells against H2O2-induced oxidative stress and its related mechanisms. C and R as individual compounds as well as CR combinations at different ratios were screened for their protective effects against H2O2 (2.5 mM) induced cell death assessed by cell viability assays. The synergistic interaction was analysed using the combination index model. The effects of optimal CR combinations on caspase-3 activity, ROS level, SOD activity, NAD cellular production, expression of Nrf2 and HO-1, and Nrf2 translocation were determined. CR combinations produced a synergistic protection against that of H2O2-induced changes in cell viability, caspase-3 activity, and ROS production. The strongest effect was observed for CR with the ratio of 8 : 2. Further experiments showed that CR 8 : 2 exhibited significantly greater effects in increasing Nrf2 translocation and expressions of Nrf2 and HO-1 proteins, as well as SOD activity and total cellular NAD production, than that of C or R alone. The findings demonstrate that combination of C and R produced a strong synergy in activity against H2O2-induced oxidative stress in EAhy926 cells. The mechanism of this synergy involves the activation of Nrf2-HO-1 signaling pathway and promotion of antioxidant enzymes. Further studies on CR synergy may help develop a new combination therapy for endothelial dysfunction and other conditions related to oxidative stress

Evaluation of phytosomal curcumin as an anti-inflammatory agent for chronic glial activation in the GFAP-IL6 mouse model

Chronic glial activation is characterized by an increased number of activated microglia and astroglia; these secrete free radicals and cytotoxic cytokines, subsequently causing neuronal damage. This study investigated the hypothesis that a soy-lecithin based phytosomal curcumin formulation can decrease glial activation in the brains of GFAP-IL6 mice, a model of chronic glial activation, which exhibits gliosis in various regions of the brain. Three doses of Meriva curcumin (MC) (874, 436, and 218 PPM) were fed to 3-month-old GFAP-IL6 and wild-type (WT) mice for 4 weeks. As markers of glial activation, the total numbers of Iba-1+ and TSPO+ microglia and macrophages, and GFAP+ astrocytes, were determined in the cerebellum and hippocampus by immunohistochemistry and unbiased stereology. Furthermore, the morphology of the glial cells was assessed by confocal microscopy and Sholl analysis. Administration of phytosomal curcumin led to a dose-dependent reduction in neuroinflammatory markers. Phytosomal curcumin (874 PPM) decreased the number of microglia by 26.2% in the hippocampus and by 48% in the cerebellum of the GFAP-IL6 mice compared with the GFAP-IL6 mice on normal food. Additionally, GFAP+ astrocyte numbers in the hippocampus of the GFAP-IL6 mice were decreased by 42%. The GFAP-IL6 mice exhibited a different microglial morphology to the WT mice, showing an increased soma size and perimeter. This difference was significantly reduced by the 874 PPM phytosomal curcumin dose. Our findings demonstrate that phytosomal curcumin is able to attenuate the inflammatory pathology, and potentially reverse the detrimental effects of chronic glial activation

Myrtinols A-F : new anti-inflammatory peltogynoid flavonoid derivatives from the leaves of Australian Indigenous plant Backhousia myrtifolia

Our in-house ethnopharmacological knowledge directed our anti-inflammatory investigation into the leaves of Backhousia mytifolia. Bioassay guided isolation of the Australian indigenous plant Backhousia myrtifolia led to the isolation of six new rare peltogynoid derivatives named myrtinols A–F (1–6) along with three known compounds 4-O-methylcedrusin (7), 7-O-methylcedrusin (8) and 8-demethylsideroxylin (9). The chemical structures of all the compounds were elucidated by detailed spectroscopic data analysis, and absolute configuration was established using X-ray crystallography analysis. All compounds were evaluated for their anti-inflammatory activity by assessing the inhibition of nitric oxide (NO) production and tumor necrosis factor- α (TNF-α) in lipopolysaccharide (LPS) and interferon (IFN)-γ activated RAW 264.7 macrophages. A structure activity relationship was also established between compounds (1–6), noting promising anti-inflammatory potential by compounds 5 and 9 with an IC50 value of 8.51 ± 0.47 and 8.30 ± 0.96 µg/mL for NO inhibition and 17.21 ± 0.22 and 46.79 ± 5.87 µg/mL for TNF-α inhibition, respectively

Synergistic anti-inflammatory activity of ginger and turmeric extracts in inhibiting lipopolysaccharide and interferon-γ-induced proinflammatory mediators

This study aims to investigate the combined anti-inflammatory activity of ginger and turmeric extracts. By comparing the activities of individual and combined extracts in lipopolysaccharide and interferon-gamma-induced murine RAW 264.7 cells, we demonstrated that ginger-turmeric combination was optimal at a specific ratio (5:2, w/w) in inhibiting nitric oxide, tumour necrosis factor and interleukin 6 with synergistic interaction (combination index < 1). The synergistic inhibitory effect on TNF was confirmed in human monocyte THP-1 cells. Ginger-turmeric combination (5:2, w/w) also upregulated nuclear factor erythroid 2-related factor 2 activity and heme oxygenase-1 protein expression. Additionally, 6-shogaol, 8-shogaol, 10-shogaol and curcumin were the leading compounds in reducing major proinflammatory mediators and cytokines, and a simplified compound combination of 6-s, 10-s and curcumin showed the greatest potency in reducing LPS-induced NO production. Our study provides scientific evidence in support of the combined use of ginger and turmeric to alleviate inflammatory processes

Tristaenone A : a new anti-inflammatory compound isolated from the Australian Indigenous plant Tristaniopsis laurina

Inspired by ethnopharmacological knowledge, we conducted a bioassay-guided fractionation of the leaves of Tristaniopsis laurina which led to the discovery of a new anti-inflammatory compound, tristaenone A (1). The structure was elucidated by detailed spectroscopic data analysis, and the absolute configuration was established using X-ray crystallography analysis. Tristaenone A (1) suppressed LPS and IFN-γ-induced NO, TNF-α and IL-6 production in RAW 264.7 cells with IC50 values of 37.58 ± 2.45 μM, 80.6 ± 5.82 μM and 125.65 ± 0.34 μM, respectively. It also inhibited NF-κB nuclear translocation by 52.93 ± 14.14% at a concentration of 31.85 μM

Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model

Chronic glial activation is characterized by increased numbers of activated glial cells, secreting free radicals and cytotoxic cytokines, subsequently causing neuronal damage. In order to investigate the anti-inflammatory activity of Longvida® Optimised Curcumin (LC), we fed 500 ppm of LC to 2-month-old wild type and GFAP-IL6 mice for 6 months. LC feeding led to a significant reduction in the number of Iba-1+ microglia by 26% in the hippocampus and by 48% in the cerebellum, GFAP+ astrocytes by 30%, and TSPO+ cells by 24% in the hippocampus and by 31% in the cerebellum of the GFAP-IL6 mice. The morphology of the cells was assessed and LC significantly decreased the dendritic length of microglia and the convex area, convex perimeter, dendritic length, nodes and number of processes of astrocytes in the hippocampus while decreasing the soma area and perimeter in the cerebellum, in LC-fed GFAP-IL6 mice. In addition, LC feeding increased pre- and postsynaptic protein levels and improved balance measured by Rotarod. Together, these data suggest that LC is able to attenuate the inflammatory pathology and ameliorate neurodegeneration and motor deficits in GFAP-IL6 mice. For patients with neuro-inflammatory disorders, LC might potentially reverse the detrimental effects of chronic glial activation

Metabolic similarity of plant and human : implications for efficacy and regulatory compliance of herbal therapies

Forecasting what biological effects an active metabolite compartmentalized in a medicinal plant may have on human health requires intensive research and clinical trials. There are inconsistencies in the application of herbal medicine in the treatment of disease mostly due to the metabolic composition. Different herbal strains, growing media and environmental conditions will alter the metabolite composition of herbal extracts. A modeling approach to identify the genes, enzymes and signaling pathways involved in the biosynthesis of the medicinal plant metabolites could harmonize the process of predicting the metabolite composition. The structural similarity of primary and secondary plant herbal metabolites does not always provide complete assurance of what pharmacological effect they may have on the respective human metabolic system. Many of the medicinal plant metabolites are either unknown or not searchable through current computational resources. In this review, we have discussed that a system based biological approach comparing human and plant metabolic signaling networks that could be additionally productive to ascertain the regulatory and biological processes conferred by a metabolite and their bioactivity pathways in living systems. A combination of a both systems and structural based approaches can generate new models that render a better metabolite composition bioactivity reduction, thereby enhancing the efficacy, safety, and toxicity of herbal medicine processing

Vitamin D2-Enriched Button Mushroom (Agaricus bisporus) Improves Memory in Both Wild Type and APPswe/PS1dE9 Transgenic Mice

Vitamin D deficiency is widespread, affecting over 30% of adult Australians, and increasing up to 80% for at-risk groups including the elderly (age>65). The role for Vitamin D in development of the central nervous system is supported by the association between Vitamin D deficiency and incidence of neurological and psychiatric disorders including Alzheimer's disease (AD). A reported positive relationship between Vitamin D status and cognitive performance suggests that restoring Vitamin D status might provide a cognitive benefit to those with Vitamin D deficiency. Mushrooms are a rich source of ergosterol, which can be converted to Vitamin D2 by treatment with UV light, presenting a new and convenient dietary source of Vitamin D2. We hypothesised that Vitamin D2-enriched mushrooms (VDM) could prevent the cognitive and pathological abnormalities associated with dementia. Two month old wild type (B6C3) and AD transgenic (APPSwe/PS1dE9) mice were fed a diet either deficient in Vitamin D2 or a diet which was supplemented with VDM, containing 1±0.2 μg/kg (∼54 IU/kg) vitamin D2, for 7 months. Effects of the dietary intervention on memory were assessed pre- and post-feeding. Brain sections were evaluated for amyloid β (Aβ) plaque loads and inflammation biomarkers using immuno-histochemical methods. Plasma vitamin D metabolites, Aβ40, Aβ42, calcium, protein and cholesterol were measured using biochemical assays. Compared with mice on the control diet, VDM-fed wild type and AD transgenic mice displayed improved learning and memory, had significantly reduced amyloid plaque load and glial fibrillary acidic protein, and elevated interleukin-10 in the brain. The results suggest that VDM might provide a dietary source of Vitamin D2 and other bioactives for preventing memory-impairment in dementia. This study supports the need for a randomised clinical trial to determine whether or not VDM consumption can benefit cognitive performance in the wider population

Synergistic inhibition of pro-inflammatory pathways by ginger and turmeric extracts in RAW 264.7 cells

Synergy plays a prominent role in herbal medicines to increase potency and widen the therapeutic windows. The mechanism of synergy in herbal medicines is often associated with multi-targeted behavior and complex signaling pathways which are challenging to elucidate. This study aims to investigate the synergistic mechanism of a combination (GT) of ginger (G) and turmeric (T) extracts by exploring the modulatory activity in lipopolysaccharides (LPS)-induced inflammatory pathways and key molecular targets. A Bioplex ProTM mouse cytokine 23-plex assay was utilized to assess the broad anti-cytokine activity of GT in LPS and interferon (IFN)-gamma (both at 50 ng/mL)-activated RAW 264.7 cells. The inhibitory effects of individual and combined G and T on major proinflammatory mediators including nitric oxide (NO), tumor necrosis factor (TNF) and interleukin (IL)-6 were tested using Griess reagents and ELISA assays, respectively. Immunofluorescent staining and Western blot were used to investigate the modulatory effect of GT on key proteins in the LPS/TLR4 signaling transduction. The regulation of murine microRNA miR-155-5p was tested using real-time PCR. The IC50 value and combination index (CI) values were used to demonstrate potency and synergistic interaction, respectively. GT synergistically attenuated a range of pro-inflammatory mediators including inducible NO, major cytokines (TNF and IL-6) and secondary inflammatory cytokines (GM-CSF and MCP-1). GT significantly inhibited LPS-induced NF-kB p65 translocation, the activation of TLR4, TRAF6, and phosphorylation of JNK and c-JUN. Moreover, the suppressive effect of GT on each of the protein targets in this axis was stronger than that of the individual components. Real-time PCR analysis showed that GT suppressed miR-155-5p to a greater extent than G or T alone in LPS-stimulated cells. Our study demonstrates the synergistic mechanism of GT in downregulating LPS-induced proinflammatory pathways at the miRNA and protein levels. Our results establish a scientific basis for the combined application of G and T as an advanced therapeutic candidate in inflammatory diseases with broad and synergistic anti-inflammatory activity and multi-targeted mechanisms