N-Feruloylserotonin inhibits lipopolysaccharide-induced inflammation via SIRT1-stimulated FOXO1 and NF-κB signaling pathways in RAW 264.7 cells.

Macrophages become activated by a variety of stimuli such as lipopolysaccharide (LPS) and participate in the process of immune responses. Activated macrophages produce various inflammatory mediators. In the present study, we investigated the anti-inflammatory mechanism of a serotonin derivative, N-feruloylserotonin, isolated from safflower seeds in RAW 264.7 macrophages. N-Feruloylserotonin treatment significantly attenuated these effects on LPS-induced reactive oxygen species, nitric oxide, and prostaglandin E2 production in RAW 264.7 macrophages. Furthermore, N-feruloylserotonin significantly decreased the abnormal expression of mitogen-activated protein kinase, such as phosphor (p)-c-Jun N-terminal kinase and p-extracellular-signal regulated kinase activation. Further research revealed that N-feruloylserotonin could stimulate sirtuin1 (SIRT1), then promote the forkhead box protein O1 (FOXO1), and suppress nuclear factor-kappa B (NF-kB) signaling pathways. The present study suggests that N-feruloylserotonin may be a new anti-inflammatory component and a promising candidate for anti-inflammatory therapeutic agents through the regulation of SIRT1-stimulated FOXO1 and NF-kB signaling pathways.

A systematic review on anti-diabetic action of 7-O-galloyl-D-sedoheptulose, a polyphenol from Corni Fructus, in type 2 diabetic mice with hepatic and pancreatic damage.

Traditional medicines are recently being focused on to treat diabetes and its complications because of their lack of toxic and/or side effects. This report describes the effects of 7-O-galloyl-D-sedoheptulose (GS), a polyphenolic compound isolated from Corni Fructus, on type 2 diabetic db/db mice with hepatic and pancreatic damage. We examined several biochemical factors and oxidative stress- and inflammation-related markers. In the serum, levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, and interleukin-6 were down-regulated, while adiponectin was augmented by GS treatment. In addition, GS suppressed the reactive oxygen species and lipid peroxidation in the serum, liver, and pancreas, but increased the pancreatic insulin and pancreatic C-peptide contents. These results were derived from attenuating the expression of nicotinamide adenine dinucleotide phosphate oxidase subunit proteins, Nox-4 and p22phox. Augmented nuclear factor (NF)-E2-related factor 2 and heme oxygenase-1 were reduced with a decrease in oxidative stress during GS treatment. NF-κB-related pro-inflammatory factors were also alleviated in hepatic tissue. Moreover, GS modulated the protein expressions of pro-inflammatory NF-κB, cyclooxygenase-2, inducible nitric oxide synthase, c-Jun N-terminal kinase (JNK), phosphor-JNK, activator protein-1, transforming growth factor-ß1, and fibronectin. Based on these results, we demonstrated that the anti-diabetic action of GS may be due to its anti-oxidative stress property and anti-inflammatory action.

Therapeutic Potential of Two Derivative Prescriptions of Rokumijiogan, Hachimijiogan and Bakumijiogan against Renal Damage in Nephrectomized Rats.

Background: Hachimijiogan (HJG) and Bakumijiogan (BJG), two derivative prescriptions of Rokumijiogan (RJG), were selected to investigate their renoprotective potential in the 5/6 nephrectomized (5/6Nx) rat model. Methods: Rats were treated with HJG and BJG orally at 150 mg/kg body weight/day once daily for 10 weeks after resection of 5/6 of the renal volume, and their renoprotective effects were compared with 5/6Nx vehicle-treated and sham-operated control rats. Results: Improvements in renal lesions, glomerulosclerosis, tubulointerstitial injury, and arteriosclerotic lesions estimated by histologic scoring indices in the HJG-treated group were compared with those in the BJG-treated group. HJG- and BJG-treated groups ameliorated the renal function parameters. Elevated levels of renal oxidative stress-related biomarkers were reduced, while decreased antioxidant defence systems (superoxide dismutase and the glutathione/oxidized glutathione ratio) were increased in the HJG-treated group rather than the BJG-treated group. In contrast, BJG administration significantly reduced expression of the inflammatory response through oxidative stress. The HJG-treated group showed a decrease in inflammatory mediators through the JNK pathway. To gain a deeper understanding of their therapeutic action, the effects of the main components detected in HJG and BJG were evaluated using the LLC-PK1 renal tubular epithelial cell line, which is the renal tissue most vulnerable to oxidative stress. Corni Fructus and Moutan Cortex-originated compositions afforded important protection against oxidative stress induced by peroxynitrite. Conclusions: From our described and discussed analyses, it can be concluded that RJG-containing prescriptions, HJG and BJG are an excellent medicine for chronic kidney disease. In the future, appropriately designed clinical studies in people with chronic kidney disease are necessary to evaluate the renoprotective activities of HJG and BJG.

PPARα Agonist, MHY3200, Alleviates Renal Inflammation during Aging via Regulating ROS/Akt/FoxO1 Signaling.

PPARα is a ligand-dependent transcription factor and its activation is known to play an important role in cell defense through anti-inflammatory and antioxidant effects. MHY3200 (2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2,2-difluoroacetic acid), a novel benzothiazole-derived peroxisome proliferator-activated receptor α (PPARα) agonist, is a synthesized PPARα activator. This study examined the beneficial effects of MHY3200 on age-associated alterations in reactive oxygen species (ROS)/Akt/forkhead box (FoxO) 1 signaling in rat kidneys. Young (7-month-old) and old (22-month-old) rats were treated with MHY3200 (1 mg/kg body weight/day or 3 mg/kg body weight/day) for two weeks. MHY3200 treatment led to a notable decrease in triglyceride and insulin levels in serum from old rats. The elevated kidney ROS level, serum insulin level, and Akt phosphorylation in old rats were reduced following MHY3200 treatment; moreover, FoxO1 phosphorylation increased. MHY3200 treatment led to the increased level of FoxO1 and its target gene, MnSOD. MHY3200 suppressed cyclooxygenase-2 expression by activating PPARα and inhibiting the activation of nuclear factor-κB (NF-κB) in the kidneys of old rats. Our results suggest that MHY3200 ameliorates age-associated renal inflammation by regulating NF-κB and FoxO1 via ROS/Akt signaling.

Therapeutic potential of Chinese prescription Kangen-karyu for patient with lifestyle-induced metabolic syndrome.

We report a case of a 65-year-old patient with hypertension, dyslipidemia, type 2 diabetes, chronic kidney disease, and hyperuricemia, who showed an improvement in lifestyle-induced metabolic syndrome on the administration of 7.5 g of Kangen-karyu extract per day for 6 months. The levels of serum total cholesterol, low-density lipoprotein-cholesterol, and triglycerides were decreased. The systolic/diastolic blood pressure was decreased following administration. Other parameters such as estimated glomerular filtration rate, creatinine, uric acid, aspartate transaminase, alanine aminotransferase, γ-glutamyl transpeptidase, and creatine phosphokinase were improved by the administration of Kangen-karyu extract. At that time, the physical and subjective symptoms had partially disappeared. We present evidence supporting the use of Kangen-karyu extract against metabolic syndrome.

Therapeutic effect of Chinese prescription Kangen-karyu in patients with diabetic nephropathy.

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. A number of new therapies have been developed based on the pathogenic factors of diabetic nephropathy such as intensive glycemic control, precise hypertension control, lifestyle modifications including exercise and an energy-restricted diet, and numerous novel agents. The utilization of traditional Chinese medicine for patients with diabetic nephropathy has also received increasing attention due to its wide availability, weak side-effects, and proven therapeutic mechanisms and benefits. In this paper, we report the case of patients with diabetic nephropathy, stage 2 or 3. Kangen-karyu extract (7.5 g/day) was administered three times per day for 6 months. The estimated glomerular filtration rate was increased at the 6-month follow-up. The serum creatinine level decreased following administration. At that time, somatic and subjective symptoms had partially disappeared. Here, we present evidence that Kangen-karyu exerts a renoprotective effect against the development of diabetic nephropathy.

A systematic review on anti-Alzheimer's disease activity of prescription Kangen-karyu.

Traditional Chinese and Japanese medicines have become prime sources of drug discovery and there is a pressing need to investigate the effectiveness of these traditional medicines for modern drug discovery. Recently, among various traditional formulations, studies on Kangen-karyu (Guan-Yuan-Ke-Li), a mixture of six medicinal herbs (Salviae Miltiorrhizae Radix, Cnidii Rhizoma, Paeoniae Radix, Carthami Flos, Aucklandiae Radix, and Cyperi Rhizoma), have been growing to assess its neuroprotective role. This prompted us to undertake a thorough review of various targets of Kangen-karyu regarding its effectiveness against Alzheimer's disease, particularly focusing on cholinesterases, beta-site amyloid precursor protein cleaving enzyme 1, and glycogen synthase kinase 3ß. This review provides new insights into Kangen-karyu medication as a prospective anti-Alzheimer's medication and indicates the need for in-depth in vivo investigation in the future.

Efficacy of Chinese prescription Kangen-karyu for patient with metabolic syndrome.

Metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. The risk factors include hypertension, dyslipidemia, hyperglycemia, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. The utilization of traditional Chinese medicine to treat metabolic syndrome has received increasing attention due to its wide availability. In this paper, we report the case of a 68-year-old patient with hypertension, hypercholesterolemia, borderline diabetes, and obesity, who showed an improvement in metabolic syndrome on the administration of 7.5 g of Kangen-karyu extract per day. After 6 months, the levels of serum total cholesterol, low-density lipoprotein-cholesterol, triglycerides, hemoglobin A1c were decreased. The abdominal circumference and body weight were decreased following administration. At that time, the somatic and subjective symptoms had partially disappeared. Herein, we present and discuss the evidence supporting the use of Kangen-karyu extract against metabolic syndrome.

Root Bark of Paeonia suffruticosa Extract and Its Component Methyl Gallate Possess Peroxynitrite Scavenging Activity and Anti-inflammatory Properties through NF-κB Inhibition in LPS-treated Mice.

A peroxynitrite (ONOO-)-generating system induced by 3-morpholinosydnonimine, was used to evaluate the ONOO- scavenging properties of plants that have been widely used as traditional medicine in Korea for the treatment of several diseases. The most effective medicinal plants were Paeonia suffruticosa Andrew, followed in order by Lonicera japonica Thunb., Curcuma zedoaria (Christm.) Roscoe, and Pueraria thunbergiana Benth. In addition, root bark of P. suffruticosa was partitioned with organic solvents of different polarities, and the ethyl acetate (EtOAc) fraction showed the strongest ONOO- scavenging activity. Methyl gallate, a plant-derived phenolic compound identified from the EtOAc fraction, exerted strong ONOO- scavenging activity. The in vivo therapeutic potential of methyl gallate was investigated using lipopolysaccharide-treated mice. Oral administration of methyl gallate protected against acute renal injury and exhibited potential anti-inflammatory properties through an increase in antioxidant activity and decrease in nuclear factor-kappa B activity.

Safflower (Carthamus tinctorius L.) seed attenuates memory impairment induced by scopolamine in mice via regulation of cholinergic dysfunction and oxidative stress.

Cholinergic dysfunction and oxidative stress are the most common causes of Alzheimer's disease (AD). Safflower seed contains various anti-oxidant and cholinergic improvement compounds, such as serotonin and its derivatives. In the present study, we investigated the protective effects and mechanisms of a safflower seed extract on scopolamine-induced memory impairment in a mouse model. The safflower seed extract was orally administered at a dose of 100 mg kg-1 day-1, and then behavior tests (such as T-maze and novel object recognition tests) were conducted. Acetyl cholinesterase (AChE) activity, reactive oxygen species (ROS) production, and antioxidant enzymes in the brain were measured. In behavior tests, the novel route exploration and object recognition were improved by the administration of the safflower seed extract, which suggests that the safflower seed extract improves memory function in the scopolamine-treated mouse model. In addition, the safflower seed extract-administered group showed inhibition of the AChE activity and improved cholinergic dysfunction. Furthermore, the administration of the safflower seed extract resulted in lower ROS production and higher antioxidant enzyme levels as compared to the scopolamine-treated group, suggesting the protective role of the safflower seed extract against oxidative stress. The results of the present study suggest that the safflower seed extract improves scopolamine-induced memory deficits via the inhibition of cholinergic dysfunction and oxidative stress. Therefore, safflower seeds might become a promising agent for memory improvement in AD patients.

Protective Effects of Serotonin and its Derivatives, N-Feruloylserotonin and N-(p-Coumaroyl) Serotonin, Against Cisplatin-Induced Renal Damage in Mice.

This study examined whether serotonin and two of its derivatives, N -feruloylserotonin and N -( p -coumaroyl) serotonin, have a renoprotective effect in a mouse model of cisplatin-induced acute renal failure. Cisplatin (20 mg/kg body weight) was administered by intraperitoneal injection to male BALB/c mice that had received oral serotonin, N -feruloylserotonin or N -( p -coumaroyl) serotonin (7.5 mg/kg body weight per day) during the preceding 2 days. At 3 days after the cisplatin injection, serum and renal biochemical factors, oxidative stress, inflammation and apoptosis-related protein expression were evaluated, and histological examinations were performed. Cisplatin caused reduction in body weight and an increase in kidney weight; however, N -( p -coumaroyl) serotonin and N -feruloylserotonin attenuated these effects. Moreover, the serotonin derivatives significantly decreased serum urea nitrogen and creatinine levels. They also significantly reduced the level of reactive oxygen species and upregulated the expression of glutathione peroxidase in the kidney. Furthermore, the serotonin derivatives improved the abnormal expression of mitogen-activated protein kinases activation-dependent inflammation- and apoptosis-related protein and caused less renal damage. These results provide important evidence that N -( p -coumaroyl) serotonin and N -feruloylserotonin exert a pleiotropic effect on several parameters related to oxidative stress, inflammation and apoptosis. The derivatives also have a renoprotective effect in cisplatin-treated mice; however, this effect is higher with N -( p -coumaroyl) serotonin.

Preventive effect of oligonol on nitric oxide and reactive oxygen species production through regulation of nuclear factor kappa B signaling pathway in RAW 264.7 macrophage cells against sodium nitroprusside.

Oligonol, a low-molecular weight polyphenol isolated from lychee fruit, has been shown to possess beneficial properties, including anti-oxidative, anti-diabetic, and hepatoprotective properties in vitro and in vivo. This study was performed to investigate the anti-inflammatory effects of oligonol using sodium nitroprusside (SNP)-stimulated RAW 264.7 macrophage cells. Our results demonstrated that exposure of SNP to RAW 264.7 cells significantly decreased cell viability, and increased nitric oxide (NO) and reactive oxygen species (ROS) production. However, treatment with oligonol inhibited cell death and suppressed the over-production of NO and ROS induced by SNP in a dose-dependent manner. Consistent with these findings, oligonol significantly downregulated the mRNA levels of pro-inflammatory mediators, inducible nitric oxide synthase and cyclooxygenase-2, when compared with the SNP-treated control group. Furthermore, suppression of nuclear factor-κB (NF-κB) activation was also observed after treatment with oligonol in RAW 264.7 macrophage cells. These results suggest that oligonol attenuated SNP-induced oxidative stress and inflammatory responses via regulation of the NF-κB signalling pathway. On the basis of such potent anti-oxidant and anti-inflammatory properties, we propose that oligonol may contribute in the prevention and treatment of inflammation-related disorders.

Safflower seed extract synergizes the therapeutic effect of cisplatin and reduces cisplatin-induced nephrotoxicity in human colorectal carcinoma RKO cells and RKO-transplanted mice.

Safflower seed is effective against oxidative stress, mediating the activation of the apoptotic signaling pathway in the renal tissues of cisplatin-treated mice. The anticancer activity of safflower in various cancer cell lines has also been reported. The present study was conducted to evaluate the potential synergistic anticancer effects of the co-treatment of safflower seed extracts and cisplatin in RKO cells and in BALB/c mice bearing RKO cell-derived human colorectal tumors. In the cellular system, RKO cells were treated with safflower seed extract in the presence or absence of cisplatin for 48 h and the cytotoxicity was evaluated by using microscopy. In the in vivo system, mice were injected with RKO cells and subsequently orally administered 100 or 200 mg/kg body weight safflower seed extract plus cisplatin-treated or untreated mice for 3 days to examine the inhibitory effect on the tumor. Treatment with safflower seed extract or cisplain to RKO cells resulted in a greater cell death than in with untreated cells. In the RKO cells co-treated with both safflower seed extract and cisplatin, greater cell damage was observed. In addition, mice co-administered safflower seed extract and cisplatin had lower concentrations of serum creatinine, which were indicative of less damage to the kidney, and had a lower solid tumor mass and higher expression of the caspase-3 protein. The results showed that safflower seed extract was highly toxic to RKO cells and inhibited tumor growth in cisplatin-treated mice through renoprotective effects.

Rosmarinic Acid Derivatives' Inhibition of Glycogen Synthase Kinase-3ß Is the Pharmacological Basis of Kangen-Karyu in Alzheimer's Disease.

Inhibition of glycogen synthase kinase 3ß (GSK-3ß) is considered to be the central therapeutic approach against Alzheimer's disease (AD). In the present study, boiled water extracts of the Kangen-karyu (KK) herbal mixture and its constituents were screened for GSK-3ß inhibitory activity. KK is used in traditional Kampo and Chinese medicines for improving cognitive function. The GSK-3ß inhibition potential was evaluated by using the Kinase-Glo luminescent kinase assay platform. Furthermore, enzyme kinetics and in silico modeling were performed by using AutoDockTools to demonstrate the mechanism of enzyme inhibition. KK extract significantly inhibited GSK-3ß in a concentration-dependent manner (IC50: 17.05 ± 1.14 µg/mL) when compared with the reference drug luteolin (IC50: 2.18 ± 0.13 µM). Among the six components of KK, extracts of Cyperi Rhizoma and Salviae Miltiorrhizae Radix significantly inhibited GSK-3ß with IC50 values of 20.68 ± 2.50 and 7.77 ± 1.38 µg/mL, respectively. Among the constituents of the roots of S. miltiorrhiza water extract, rosmarinic acid, magnesium lithospermate B, salvianolic acid A, salvianolic acid B, and salvianolic acid C inhibited GSK-3ß with IC50 values ranging from 6.97 to 135.5 µM. Salvianolic acid B was found to be an ATP-competitive inhibitor of GSK-3ß and showed the lowest IC50 value (6.97 ± 0.96 µM). In silico modeling suggested a mechanism of action by which the hydrophobic, π⁻cation, and hydrophilic interactions of salvianolic acid B at ATP and substrate sites are critical for the observed GSK-3ß inhibition. Therefore, one of the mechanisms of action of KK against AD may be the inhibition of GSK-3ß and one of the active components of KK is the root of S. miltiorrhiza and its constituents: rosmarinic acid, magnesium lithospermate B, and salvianolic acids A, B, and C. Our results demonstrate the pharmacological basis for the use of KK against AD.

Oligonol, a low-molecular-weight polyphenol derived from lychee peel, attenuates diabetes-induced pancreatic damage by inhibiting inflammatory responses via oxidative stress-dependent mitogen-activated protein kinase/nuclear factor-kappa B signaling.

This study investigated the effects of oligonol, a low-molecular-polyphenol derived from lychee peel, against diabetes-induced pancreatic damage via oxidative stress-induced inflammation. Oligonol was orally administered at 10 or 20 mg/kg body weight/day for 10 days to streptozotocin-induced diabetic rats, and the rats were compared with nondiabetic and diabetic control rats. The diabetic rats showed loss of body weight and increased pancreatic weight, and the oral administration of oligonol attenuated these parameters. Moreover, the administration of oligonol caused a significant decrease in the serum glucose level and a significant increase in the serum and pancreatic insulin and C-peptide levels in the diabetic rats. Oligonol also significantly reduced the enhanced levels of reactive oxygen species and 2-thiobarbituric acid reactive substance, which are oxidative stress biomarkers, in the serum and pancreas. Oligonol treatment reduced the overexpression of phospho-p38, phospho-ERK1/2, phospho-inhibitor of nuclear factor-kappa B (NF-κB), NF-κBp65, and NF-κBp65-induced inflammatory protein such as cyclooxygenase-2, inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-6. Furthermore, oligonol treatment led to significantly attenuated histological damage in the pancreas. On the basis of these results, we conclude that a plausible mechanism of oligonol's antidiabetic action may be its antioxidative stress-related anti-inflammatory action.

Mechanism of Action of Magnesium Lithospermate B against Aging and Obesity-Induced ER Stress, Insulin Resistance, and Inflammsome Formation in the Liver.

Magnesium lithospermate B (MLB) is the biologically active compound of the water-soluble fraction of Salvia miltiorrhiza. Magnesium lithospermate B exhibits various biological functions, including antidiabetic, neuroprotective, and antioxidant effects. However, its beneficial effects on insulin sensitivity and related signaling pathways in the liver need to be elucidated. Our previous study reported that MLB is a PPARß/δ agonist in fibroblasts. Because insulin-sensitizing and anti-inflammatory effects of PPARß/δ has been reported in the liver, we investigated whether MLB has a beneficial effect on insulin-, ER stress- and inflammasome-related signaling in the livers of aging and obese animal models. Western blotting and protein-ligand docking simulation showed that MLB activated PPARß/δ and improved glucose tolerance in the livers of aging and obese animal models. MLB supplementation ameliorated aging or obesity-induced disruption of insulin signaling in the liver. Consistently, aging and obesity-induced increase in the protein levels of a gluconeogenic phosphoenolpyruvate carboxykinase was decreased by MLB. When molecular signaling pathways related to insulin signaling were examined in the liver, MLB supplementation suppressed ER stress- and inflammasome-related signaling molecules induced by aging and obesity. These results suggest that MLB may improve insulin resistance in the liver at least partially by suppressing ER stress and inflammasome formation in aging and obese animal models.

Increase in the hydroxyl radical-scavenging activity of Panax ginseng and ginsenosides by heat-processing.

Panax ginseng C.A. Meyer (Araliaceae), mainly cultivated in Korea and Northeast China, is processed before use based on its long history of ethnopharmacological evidence. Ginsenosides have been regarded as the main active components responsible for the pharmacological activities of ginseng. Although the Maillard reaction is known as a major source of compounds related to enhanced antioxidant activity by heat treatment in various crude drugs or foods, the chemical and free radical-scavenging activity changes of ginsenosides brought about by the Maillard reaction have not yet been elucidated. This paper gives a review of our recent findings, with emphasis on the hydroxyl radical (•OH)-scavenging activity changes of ginsengs and ginsenosides by heat-processing using an electron spin resonance spectrometer. 20(S)- Rg3 showed the strongest activity, and the next was in the decreasing order of Rb1, Rg1, Rc, Rb2, and Rd. The •OH-scavenging activities of ginsenosides were related to the ferrous metal ion-chelating activities of their aglycone, 20(S)-protopanaxadiol. In addition, the ferrous metal ion-chelating activities of ginsenosides were thought to be influenced by their types of hydrophilic sugar moieties. Moreover, Rb1 was changed into 20(S)-Rg3, 20(R)-Rg3, Rk1, and Rg5 by heat-processing, and the sugar moieties at carbon-20 were separated. The generated amount of 20(S)-Rg3 was higher than when Rb1 was heat-processed without amino acids, and a significant increase in Maillard reaction products was noted. Based upon chemical and •OH-scavenging activity tests using Maillard reaction model experiments, the scientific evidence underlying the increase in free radical-scavenging activity of ginseng induced by heat-processing was elucidated.

Comparison of the Effects of Nonfermented and Fermented Panax ginseng Root Against Hypertriglycemia in High-Fat Diet-Fed Mice.

Panax ginseng (P. ginseng C.A. Meyer, Araliaceae) is used as a therapeutic agent for various diseases. P. ginseng saponins, known as ginsenosides, are the main bioactive compounds responsible for its pharmacological activities. In this work, we have developed a new method of P. ginseng root processing termed solid-state fermentation and examined its effects compared with nonfermented P. ginseng. Mice were fed a high-fat diet (HFD) to induce hyperlipidemia and then received 100 mg·kg bw-1·day-1 of fermented or nonfermented P. ginseng orally for 3 weeks. We assessed the activities of lipogenic pathways and lipid levels in the liver and plasma. The administration of either nonfermented or fermented P. ginseng improved hepatic lipid transfer protein profiles. Nonfermented P. ginseng exhibited significant effects on the regulation of lipid synthesis and oxidation. However, apolipoprotein A4 (apoA4) expression was increased by the administration of fermented P. ginseng. When ginsenosides were analyzed by high-performance liquid chromatography (HPLC), the amounts of the ginsenosides, Rg2, Rc, Rh1(S), Rh1(R), and Rd, were increased by fermentation, with Rd becoming a major constituent of fermented P. ginseng. These findings imply that nonfermented P. ginseng improves hypertriglycemia in HFD-fed mice through regulation of the hepatic lipogenic pathway. In contrast, the effects of fermented P. ginseng were mediated through increased apoA4, leading to decreased triglycerides. The HPLC profiles of ginsenosides suggest that the compositional changes in P. ginseng caused by fermentation processing could be useful in the development of novel triglyceride-lowering therapies.

Protective Effect of Safflower Seed on Cisplatin-Induced Renal Damage in Mice via Oxidative Stress and Apoptosis-Mediated Pathways.

Cisplatin, a platinum chelate with potent antitumor activity against cancers of the testis, ovary, urinary bladder, prostate, and head and neck, has adverse effects on the kidney, bone marrow, and digestive organs, and its use is particularly limited by nephropathy as a side effect. In the present study, safflower seed extract was administered to a mouse model of cisplatin-induced acute renal failure to investigate its activity. Cisplatin (20[Formula: see text]mg/kg body weight) was administered by intraperitoneal injection to mice that had received oral safflower seed extract (100 or 200[Formula: see text]mg/kg body weight per day) for the preceding 2 days. Three days after the cisplatin injection, serum and renal biochemical factors; oxidative stress, inflammation, and apoptosis-related protein expression; and histological findings were evaluated. Cisplatin-treated control mice showed body-weight, food intake and water intake loss, and increased kidney weight, whereas the administration of safflower seed extract attenuated these effects ([Formula: see text], [Formula: see text]). Moreover, safflower seed extract significantly decreased the renal functional parameters urea nitrogen and creatinine in the serum ([Formula: see text] and [Formula: see text], respectively). Safflower seed extract also significantly reduced the enhanced levels of reactive oxygen species in the kidney observed following cisplatin treatment, with significance. The expression of proteins related to the anti-oxidant defense system in the kidney was down-regulated following cisplatin treatment, but safflower seed extract significantly up-regulated the expression of the anti-oxidant enzyme catalase. Furthermore, safflower seed extract reduced the overexpression of phosphor (p)-p38, nuclear factor-kappa B p65, cyclooxygenase-2, inducible nitric oxide synthase, ATR, p-p53, Bax, and caspase 3 proteins, and mice treated with safflower seed extract exhibited less renal histological damage. These results provide important evidence that safflower seed extract exerts a pleiotropic effect on several oxidative stress- and apoptosis-related parameters and has a renoprotective effect in cisplatin-treated mice.

Oligonol promotes glucose uptake by modulating the insulin signaling pathway in insulin-resistant HepG2 cells via inhibiting protein tyrosine phosphatase 1B.

Insulin resistance and protein tyrosine phosphatase 1B (PTP1B) overexpression are strongly associated with type 2 diabetes mellitus (T2DM), which is characterized by defects in insulin signaling and glucose intolerance. In a previous study, we demonstrated oligonol inhibits PTP1B and α-glucosidase related to T2DM. In this study, we examined the molecular mechanisms underlying the anti-diabetic effects of oligonol in insulin-resistant HepG2 cells. Glucose uptake was assessed using a fluorescent glucose tracer, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose, and the signaling pathway was investigated by western blotting. Oligonol significantly increased insulin-provoked glucose uptake and decreased PTP1B expression, followed by modulation of ERK phosphorylation. In addition, oligonol activated insulin receptor substrate 1 by reducing phosphorylation at serine 307 and increasing that at tyrosine 895, and enhanced the phosphorylations of Akt and phosphatidylinositol 3-kinase. Interestingly, it also reduced the expression of two key enzymes of gluconeogenesis (glucose 6-phosphatase and phosphoenolpyruvate carboxykinase), attenuated oxidative stress by scavenging/inhibiting peroxynitrite, and reactive oxygen species (ROS) generation, and augmented the expression of nuclear factor kappa B. These findings suggest oligonol improved the insulin sensitivity of insulin-resistant HepG2 cells by attenuating the insulin signaling blockade and modulating glucose uptake and production. Furthermore, oligonol attenuated ROS-related inflammation and prevented oxidative damage in our in vitro model of type 2 diabetes. These result indicate oligonol has promising potential as a treatment for T2DM.