Effect of Indian gooseberry extract on improving methylglyoxal-associated leptin resistance in peripheral tissues of high-fat diet-fed rats.

Increased leptin resistance and methylglyoxal (MG) levels are observed in obese patients. However, whether MG deposits contribute to leptin resistance, oxidative stress, and inflammation in peripheral tissues remains unclear. In addition, the edible fruit of Indian gooseberry (Phyllanthus emblica L.) contains abundant bioactive components such as vitamin C, ß-glucogallin (ß-glu), gallic acid (GA), and ellagic acid (EA). Water extract of Indian gooseberry fruit (WEIG) and GA has been shown to improve cognitive decline by suppressing brain MG-induced insulin resistance in rats administered a high-fat diet (HFD). Accordingly, this study investigated the functions of WEIG and GA in inhibiting MG-induced leptin resistance, oxidative stress, and inflammation in the peripheral tissues of HFD-fed rats. The results showed that MG, advanced glycation end products (AGEs), and leptin resistance accumulation in the liver, kidney, and perinephric fat were effectively restored by elevated glyoxalase-1 (Glo-1) activity after WEIG and GA administration comparable to that of alagebrium chloride (positive control) treatment in HFD-fed rats. Furthermore, WEIG and GA supplementation increased adiponectin and antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase) and decreased inflammatory cytokines (IL-6, IL-1ß, TNF-α) in the peripheral tissues of HFD-fed rats. In conclusion, these findings demonstrated that MG may trigger leptin resistance, oxidative stress, and inflammation in peripheral tissues, which could be abolished by WEIG and GA treatment. These results show the potential of P. emblica for functional food development and improving obesity-associated metabolic disorders.

Preventive Effect of Indian Gooseberry (Phyllanthus emblica L.) Fruit Extract on Cognitive Decline in High-Fat Diet (HFD)-Fed Rats.

SCOPE: Methylglyoxal (MG)-derived advanced glycation end products (AGEs) directly bind to the receptor for advanced glycation end products (RAGE), subsequently exacerbating obesity and obesity-induced cognitive decline. Indian gooseberry (Phyllanthus emblica L.) fruit has antiobesity properties. However, the underlying mechanism by which Indian gooseberry fruit prevents obesity-induced cognitive decline remains unclear. METHODS AND RESULTS: This study aims to investigate the preventive effect of a water extract of Indian gooseberry fruit (WEIG) and its bioactive compound gallic acid (GA) on the obesity-induced cognitive decline through MG suppression and gut microbiota modulation in high-fat diet (HFD)-fed rats. Trapping MG, WEIG, and GA significantly ameliorate fat accumulation in adipose tissue and learning and memory deficits. Mechanistically, WEIG and GA administration effectively reduces brain MG and AGE levels and subsequently reduces insulin resistance, inflammatory cytokines, MDA production, and Alzheimer's disease-related proteins, but increases both antioxidant enzyme activities and anti-inflammatory cytokine with inhibiting RAGE, MAPK, and NF-κB levels in HFD-fed rats. Additionally, WEIG and GA supplementation increases the relative abundances of Bacteroidetes, Gammaproteobacteria, and Parasutterella, which negatively correlate with MG, inflammatory cytokine, and Alzheimer's disease-related protein expressions. CONCLUSION: This novel finding provides a possible mechanism by which WEIG prevents obesity-induced cognitive decline through the gut-brain axis.

Rhinacanthus nasutus and okara polysaccharides attenuate colitis via inhibiting inflammation and modulating the gut microbiota.

Plant polysaccharides have prebiotic properties for gut microbiota and immune modulation. This study aimed to investigate the prevention abilities of edible Rhinacanthus nasutus polysaccharide (RNP) and okara polysaccharide (OP) in Sprague-Dawley rats with acetic acid-induced colitis. The characterizations of RNP and OP were analyzed, including Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetry, and monosaccharide composition. The prebiotic properties of RNP and OP were determined in vitro. In addition, the pathological features of colon length and inflammatory cytokine levels in acetic acid-induced colitis were improved by intragastric preadministration of RNP and OP for 3 weeks. There was no nephrotoxicity or hepatotoxicity in rats via histopathological assessment after RNP and OP intake. Moreover, the abundance of short-chain fatty acids-producing bacteria (Lachnospiraceae, Lactobacilli, and Prevotellaceae) were increased after RNP supplementation. In conclusion, intragastric gavage of RNP and OP significantly modulated the gut microbiota and immune response, consequently alleviating the symptoms of colitis. This novel finding provides an alternative strategy and potential application of these two polysaccharides for colitis prevention and treatment.

S-Allyl cysteine in garlic (Allium sativum): Formation, biofunction, and resistance to food processing for value-added product development.

S-allyl cysteine (SAC), which is the most abundant bioactive compound in black garlic (BG; Allium sativum), has been shown to have antioxidant, anti-apoptotic, anti-inflammatory, anti-obesity, cardioprotective, neuroprotective, and hepatoprotective activities. Sulfur compounds are the most distinctive bioactive elements in garlic. Previous studies have provided evidence that the concentration of SAC in fresh garlic is in the range of 19.0-1736.3 µg/g. Meanwhile, for processed garlic, such as frozen and thawed garlic, pickled garlic, fermented garlic extract, and BG, the SAC content increased to up to 8021.2 µg/g. BG is an SAC-containing product, with heat treatment being used in nearly all methods of BG production. Therefore, strategies to increase the SAC level in garlic are of great interest; however, further knowledge is required about the effect of processing factors and mechanistic changes. This review explains the formation of SAC in garlic, introduces its biological effects, and summarizes the recent advances in processing methods that can affect SAC levels in garlic, including heat treatment, enzymatic treatment, freezing, fermentation, ultrasonic treatment, and high hydrostatic pressure. Thus, the aim of this review was to summarize the outcomes of treatment aimed at maintaining or increasing SAC levels in BG. Therefore, publications from scientific databases in this field of study were examined. The effects of processing methods on SAC compounds were evaluated on the basis of the SAC content. This review provides information on the processing approaches that can assist food manufacturers in the development of value-added garlic products.

Reduction of 3-Deoxyglucosone by Epigallocatechin Gallate Results Partially from an Addition Reaction: The Possible Mechanism of Decreased 5-Hydroxymethylfurfural in Epigallocatechin Gallate-Treated Black Garlic.

5-Hydroxymethylfurfural (5-HMF) is a harmful substance generated during the processing of black garlic. Our previous research demonstrated that impregnation of black garlic with epigallocatechin gallate (EGCG) could reduce the formation of 5-HMF. However, there is still a lack of relevant research on the mechanism and structural identification of EGCG inhibiting the production of 5-HMF. In this study, an intermediate product of 5-HMF, 3-deoxyglucosone (3-DG), was found to be decreased in black garlic during the aging process, and impregnation with EGCG for 24 h further reduced the formation of 3-DG by approximately 60% in black garlic compared with that in the untreated control. The aging-mimicking reaction system of 3-DG + EGCG was employed to determine whether the reduction of 3-DG was the underlying mechanism of decreased 5-HMF formation in EGCG-treated black garlic. The results showed that EGCG accelerated the decrease of 3-DG and further attenuated 5-HMF formation, which may be caused by an additional reaction with 3-DG, as evidenced by LC-MS/MS analysis. In conclusion, this study provides new insights regarding the role of EGCG in blocking 5-HMF formation.

Thermal treatment enhances the α-glucosidase inhibitory activity of bitter melon (Momordica charantia) by increasing the free form of phenolic compounds and the contents of Maillard reaction products.

Inhibition of α-glucosidase can slow carbohydrate metabolism, which is known as an effective strategy for diabetes treatment. The aim of this study is to evaluate the effect of thermal treatment (50, 60, and 70℃) for 15 days on the α-glucosidase inhibitory activity of bitter melon. The results show that the bitter melon heated at 70℃ for 12 days had the best α-glucosidase inhibitory effect. However, the amount of free polyphenols, 5-hydroxymethyl-2-furfural (5-HMF), and the browning degree of bitter melon generally increased with the time (15 days) and temperature of the thermal treatment, which is positively related to their antioxidant and α-glucosidase inhibitory activities. In conclusion, aged bitter melon shows great α-glucosidase inhibitory activity, which may be related to the increased free form of the involved phenolic compounds and Maillard reaction products. This suggests that thermal processing may be a good way to enhance the application of bitter melon for diabetes treatment. PRACTICAL APPLICATION: The thermal processing of bitter melon provides an application for diabetes treatment. This study demonstrated that heat-treated bitter melon can lower the blood glucose level; therefore, it can be used as a potential anti-hyperglycemic and functional food.

Effects of Hsian-tsao (Mesona procumbens Hemsl.) extracts and its polysaccharides on the promotion of wound healing under diabetes-like conditions.

The aim of the study was to evaluate the effects of Hsian-tsao (Mesona procumbens Hemsl.) and its polysaccharides on impaired wound healing in diabetes. The results indicate that ethanol extracts of Hsian-tsao (EE) and crude polysaccharides from water extracts of Hsian-tsao (WEP) had strong inhibitory effects on methylglyoxal (MG)-induced glycation and reactive oxygen species (ROS) production. EE and WEP also decreased MG-induced inflammation-related factors in RAW 264.7 macrophages and restored MG-impaired wound-healing factors in 3T3-L1 fibroblasts. Furthermore, EE and WEP were found to dose-dependently enhance the MG-impaired phagocytosis of Staphylococcus aureus and Pseudomonas aeruginosa by macrophages. Excitingly, EE and WEP significantly enhanced wound healing on the dorsal skin through regulation of macrophage inflammatory protein-2 (MIP-2), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein expressions in diabetic mice, as evidenced by the percentage reduction in wound surface area and the results of histopathologic scoring analysis. In conclusion, these results suggest that Hsian-tsao extract and its polysaccharides might be utilized in alternative natural therapy to promote wound healing in diabetic individuals.

Ursolic acid promotes apoptosis, autophagy, and chemosensitivity in gemcitabine-resistant human pancreatic cancer cells.

Gemcitabine (GEM) resistance in pancreatic adenocarcinoma mediated by the receptor for advanced glycation end products (RAGE) has been demonstrated. Therefore, investigating the safety and the potential of new auxiliary methods for pancreatic cancer treatment is urgent. Ursolic acid (UA), a natural pentacyclic triterpenoid found in apple peels, rosemary, and thyme, has been reported to have anticancer capacity. This study aimed to reveal the underlying mechanisms of UA in cell death and drug enhancement, especially in GEM-resistant pancreatic cancer cells. First, GEM-resistant cells (MIA Paca-2GEMR cells) were established by incrementally increasing GEM culture concentrations. UA treatment reduced cell viability through cell cycle arrest and endoplasmic reticulum (ER) stress, resulting in apoptosis and autophagy in a dose-dependent manner in MIA Paca-2 and MIA Paca-2GEMR cells. High RAGE expression in MIA Paca-2GEMR cells was suppressed by UA treatment. Interestingly, knocking down RAGE expression showed similar UA-induced effects in both cell lines. Remarkably, UA had a drug-enhancing effect by decreasing cell viability and increasing cell cytotoxicity when combined with GEM treatment. In conclusions, UA triggered ER stress, subsequently regulating apoptosis- and autophagy-related pathways and increasing GEM chemosensitivity in pancreatic cancer cells by inhibiting the expression of RAGE.

The preventive role of breadfruit against inflammation-associated epithelial carcinogenesis in mice.

Artocarpus communis has been identified as a rich source of flavonoids and has been gaining attention for its potential chemopreventive abilities. In this study, methanol extracts from the fruit of A. communis (MEFA) and leaf of A. communis (MELA) were prepared, and their effects on inflammation-associated skin tumorigenesis were assessed using mouse models, including 12-O-tetradecanoylphorbol-13-acetate (TPA) induced cutaneous inflammation as well as 7,12-dimethylbenz[α]anthracene (DMBA) initiated and TPA-promoted skin tumorigenesis. According to the results, both MEFA and MELA decreased the intensity of leukocyte infiltration in mouse dorsal skin and cutaneous edema induced by TPA, which appeared to be mediated by inhibition of proinflammatory genes (inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6) and proinflammatory mediators (TNF-α, IL-1ß, and Prostaglandin E2 ). In addition, topical application with MEFA or MELA effectively attenuated tumor incidence, multiplicity, volume, malignancy as well as angiogenesis of TPA-stimulated skin tumor promotion in DMBA-initiated mice. Notably, immunohistochemical stain showed that MEFA and MELA attenuated COX-2 expression of both skin and tumor tissues in different animal tests, which may be closely related to the suppression of nuclear factor kappa B/activator protein signaling networks. These findings first demonstrate that flavonoid-rich A. communis may exert potent anti-inflammatory activity through modulation of COX-2 in TPA-activated skin and tumor tissues.

EGCG-rich green tea extract stimulates sRAGE secretion to inhibit S100A12-RAGE axis through ADAM10-mediated ectodomain shedding of extracellular RAGE in type 2 diabetes.

The receptor for advanced glycation of end products (RAGE) plays a critical role in the progression of type 2 diabetes (T2D). Soluble RAGE (sRAGE) is one of the RAGE variants, which acts as a decoy domain receptor and competes with RAGE, thus contributing to prevention of T2D. In this study, we conducted clinical trials of (-)-epigallocatechin-3-gallate (EGCG) rich green tea extract (300-900 mg/day) to investigate the effect of EGCG on relationship between S100A12 RAGE ligand and diverse sRAGE in T2D. Moreover, mechanism of sRAGE production also confirmed in vitro. Our data indicated that EGCG could stimulate sRAGE circulation but inhibited RAGE ligand in T2D, and ADAM10-mediated ectodomain shedding of extracellular RAGE was mainly involved in EGCG-stimulated sRAGE circulation. The present evidence indicates that EGCG has a potential to block S100A12-RAGE axis by stimulating sRAGE production through ADAM10-mediated ectodomain shedding of extracellular RAGE. Therefore, EGCG contributes to nutritional strategies for diabetes, not only because of its efficient antioxidant activity to scavenge free radicals, but also because of its ability stimulating sRAGE release in the circulation. Additionally, ADAM10-induced ectodomain shedding of extracellular RAGE leading to sRAGE circulation should be a potential of passive mechanism of sRAGE production to block S100A12-RAGE axis-related pathogenesis of proinflammation and diabetes.

Alternanthera paronychioides protects pancreatic ß-cells from glucotoxicity by its antioxidant, antiapoptotic and insulin secretagogue actions.

The antioxidant and antiglucotoxic effects of Alternanthera paronychioides on pancreatic ß-cell were investigated. Antioxidant assays demonstrated that ethanol extracts of A. paronychioides (EEAP) exhibited the highest antioxidant activity, which also had the highest phenolic and flavonoid contents. Two major polyphenolics, ferulic acid and quercetin, were identified from EEAP by HPLC-DAD. Effects of EEAP, ferulic acid and quercetin on high glucose (25 mmol/L)-induced pancreatic ß-cell apoptosis and dysfunction were further evaluated. Results showed that EEAP and quercetin but not ferulic acid protected ß-cells from glucotoxicity through several mechanisms, including: (1) maintaining ß-cell viability; (2) suppressing reactive oxygen species production; (3) reducing characteristic features of apoptosis; (4) inhibiting the activation of caspase-9 and caspase-3 and the cleavage of poly (ADP-ribose) polymerase; (5) upregulating pancreatic and duodenal homeobox 1 gene expression and the insulin secretagogue action of pancreatic ß-cells. These findings may shed light on the preventive actions of A. paronychioides on diabetic glucotoxicity.

Pro-cellular survival and neuroprotection of citrus flavonoid: the actions of hesperetin in PC12 cells.

Hesperetin protects cells against oxidative stress by diverse mechanisms including receptor-mediated actions. PGC-1α and seladin-1 provide potential targets for intervention in oxidative stress-associated neurodegeneration. PC12 cells express TrkA and estrogen receptor (ER). It is known that TrkA triggers the MAPK/ERK1, PI-3 K/Akt, PLCγ/PKC and cAMP/PKA pathways, and membrane ER triggers the MAPK/ERK1, PKA, Akt/PKB or PKC pathway. Using PC12 cells and immunoblotting, we show that hesperetin induces the rapid (15 min) and sustained (~24 h) expression of PGC-1α (regulated by CREB) and seladin-1 (regulated by ER); hesperetin activates PI-3 K, PKA, PKC, ERK1 and CREB, and it induces PI-3 K, PKA, PGC-1α and seladin-1 via both ER and TrkA; any inhibitor of PI-3 K, PKA or PKC effectively suppresses the activation of ERK1 and CREB as well as the induction of PGC-1α and seladin-1; ERK1 inhibitors effectively suppress hesperetin-induced CREB activation and PGC-1α expression, but have no effect on the induction of seladin-1. This study reveals that hesperetin triggers ER- and TrkA-mediated parallel pathways, collaborating to induce proteins regulated by different transcriptional factors. This novel mechanism explains why hesperetin, although it is known to have relatively low antioxidant and estrogen activities, can exhibit multiple neuroprotective effects.

Inhibition of advanced glycation endproduct formation by foodstuffs.

The Maillard reaction, which is generally termed nonenzymatic browning or glycation, has been implicated in accelerated aging and diabetic complications in vivo. Although the molecular basis of glycation-induced pathogenesis is not well understood, the following have been noted: (1) protein glycation leads to the formation and accumulation of toxic advanced glycation endproducts (AGEs); (2) AGEs can permanently alter the structure and function of body proteins; and (3) the interaction between AGE-modified proteins and AGE-specific receptors (RAGEs) on the cell surface induces the overproduction of reactive oxygen species (ROSs) and inflammatory mediators, which leads to cellular disorders in biological systems. To date, studies that have examined the contribution of protein glycation to disease-states have primarily focused on the deleterious effects and related mechanisms of these glycotoxins. However, it remains unknown whether phytochemicals exert protective effects against glycotoxin-induced damage. Thus, the development and investigation of AGE inhibitors, especially the natural anti-AGE agents without adverse effects, may provide a therapeutic approach for delaying and preventing premature aging and diabetic complications. In this review, we provide an outline of anti-glycation properties of foodstuffs and/or their active components, and discuss their mechanisms of action.

Anti-inflammatory effect of the 5,7,4'-trihydroxy-6-geranylflavanone isolated from the fruit of Artocarpus communis in S100B-induced human monocytes.

The fruit of Artocarpus communis Moraceae, a traditional starch crop, is a rich source of phytochemicals, such as flavonoids and their derivatives. The aim of this study was to investigate whether 5,7,4'-trihydroxy-6-geranylflavanone (AC-GF), a geranyl flavonoid derivative isolated from the fruits of A. communis, could decrease the activation of inflammatory mediators induced by S100B (ligand of receptor for advanced glycation end products, RAGE) in THP-1 monocytes. According to the results, low levels of AC-GF (≤2.5 µM) showed a great inhibitory effect on gene expression of RAGE and down-regulated both TNF-α and IL-1ß secretion and gene expression (p < 0.05). AC-GF also decreased reactive oxygen species (ROS) production in response to S100B (p < 0.05). Additionally, Western blotting revealed that AC-GF could effectively attenuate RAGE-dependent signaling, including expression of protein kinase C (PKC) and p47phox, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), and particularly NF-κB activation (p < 0.05). In conclusion, this is the first report that AC-GF possesses great antioxidant and anti-inflammatory properties in vitro. This finding may contribute to increased implication and utilization of the fruit of A. communis Moraceae in functional foods.