A Bibenzyl Component Moscatilin Mitigates Glycation-Mediated Damages in an SH-SY5Y Cell Model of Neurodegenerative Diseases through AMPK Activation and RAGE/NF-κB Pathway Suppression.

Moscatilin can protect rat pheochromocytoma cells against methylglyoxal-induced damage. Elimination of the effect of advanced glycation end-products (AGEs) but activation of AMP-activated protein kinase (AMPK) are the potential therapeutic targets for the neurodegenerative diseases. Our study aimed to clarify AMPK signaling's role in the beneficial effects of moscatilin on the diabetic/hyperglycemia-associated neurodegenerative disorders. AGEs-induced injury in SH-SY5Y cells was used as an in vitro neurodegenerative model. AGEs stimulation resulted in cellular viability loss and reactive oxygen species production, and mitochondrial membrane potential collapse. It was observed that the cleaved forms of caspase-9, caspase-3, and poly (ADP-ribose) polymerase increased in SH-SY5Y cells following AGEs exposure. AGEs decreased Bcl-2 but increased Bax and p53 expression and nuclear factor kappa-B activation in SH-SY5Y cells. AGEs also attenuated the phosphorylation level of AMPK. These AGEs-induced detrimental effects were ameliorated by moscatilin, which was similar to the actions of metformin. Compound C, an inhibitor of AMPK, abolished the beneficial effects of moscatilin on the regulation of SH-SY5Y cells' function, indicating the involvement of AMPK. In conclusion, moscatilin offers a promising therapeutic strategy to reduce the neurotoxicity or AMPK dysfunction of AGEs. It provides a potential beneficial effect with AGEs-related neurodegenerative diseases.

Hesperidin Prevents High Glucose-Induced Damage of Retinal Pigment Epithelial Cells.

The present study aimed to determine whether hesperidin, a plant-based active flavanone found in citrus fruits, can prevent high glucose-induced retinal pigment epithelial (RPE) cell impairment. Cultured human RPE cells (ARPE-19) were exposed to a normal glucose concentration (5.5 mM) for 4 d and then soaked in either normal (5.5 mM) or high (33.3 mM) concentrations of D-glucose with or without different concentrations of hesperidin (10, 20, or 40 µM) for another 48 h. The survival rates of the cells were measured using a 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction assay. With the help of a fluorescent probe, the intracellular production of reactive oxygen species (ROS) was evaluated. Colorimetric assay kits were used to assess the antioxidant enzyme activities, and western blotting was used to measure the expression of apoptosis-related protein. Hesperidin was effective in inhibiting high glucose-induced ROS production, preventing loss of cell viability, and promoting the endogenous antioxidant defense components, including glutathione peroxidase, superoxide dismutase, catalase, and glutathione, in a concentration-dependent manner. Furthermore, high glucose triggered cell apoptosis via the upregulation of caspase-9/3, enhancement of cytochrome c release into the cytosol, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by hesperidin in a concentration-dependent manner. We conclude that through the scavenging of ROS and modulation of the mitochondria-mediated apoptotic pathway, hesperidin may protect RPE cells from high glucose-induced injury and thus may be a candidate in preventing the visual impairment caused by diabetic retinopathy.

Gigantol has Protective Effects against High Glucose-Evoked Nephrotoxicity in Mouse Glomerulus Mesangial Cells by Suppressing ROS/MAPK/NF-κB Signaling Pathways.

Gigantol is a bibenzyl compound derived from several medicinal orchids. This biologically active compound has shown promising therapeutic potential against diabetic cataracts, but whether this compound exerts beneficial effects on the other diabetic microvascular complications remains unclear. This study was carried out to examine effects of gigantol on high glucose-induced renal cell injury in cultured mouse kidney mesangial cells (MES-13). MES-13 cells were pretreated with gigantol (1, 5, 10 or 20 µmol/L) for 1 h followed by further exposure to high (33.3 mmol/L) glucose for 48 h. Gigantol concentration dependently enhanced cell viability followed by high glucose treatment in MES-13 cells. High glucose induced reactive oxygen species (ROS) generation, malondialdehyde production and glutathione deficiency were recoved in MES-13 cells pretreated with gigantol. High glucose triggered cell apoptosis via the the loss of mitochondrial membrane potential, depletion of adenosine triphosphate, upregulation of caspases 9 and 3, enhancement of cytochrome c release, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by gigantol. High glucose also induced activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in MES-13 cells, which were blocked by gigantol. The results suggest that treatment MES-13 cells with gigantol halts high glucose-induced renal dysfunction through the suppression of the ROS/MAPK/NF-κB signaling pathways. Our data are of value to the understanding the mechanism for gigantol, and would benefit the study of drug development or food supplement for diabetes and nephropathy.

The Benefits of the Citrus Flavonoid Diosmin on Human Retinal Pigment Epithelial Cells under High-Glucose Conditions.

We investigate diosmin for its effect on the ARPE-19 human retinal pigment epithelial cells exposed to high glucose, a model of diabetic retinopathy (DR). After incubation for 4 days with a normal (5 mmol/L) concentration of D-glucose, ARPE-19 cells were exposed separately to normal or high concentrations of D-glucose (30 mmol/L) with or without diosmin at different concentrations (0.1, 1, 10 µg/mL) for another 48 h. Next, we assessed cell viability, reactive oxygen species (ROS) generation and antioxidant enzyme activities. In order to examine the underlying molecular mechanisms, we meanwhile analyzed the expressions of Bax, Bcl-2, total and phosphorylated JNK and p38 mitogen-activated protein kinase (MAPK). Diosmin dose dependently enhanced cell viability following high glucose treatment in ARPE-19 cells. The activities of superoxide dismutase and glutathione peroxidase, as well as the levels of reduced glutathione were decreased, while it was observed that levels of ROS in high glucose cultured ARPE-19 cells increased. High glucose also disturbed Bax and Bcl-2 expression, interrupted Bcl-2/Bax balance, and triggered subsequent cytochrome c release into the cytosol and activation of caspase-3. These detrimental effects were ameliorated dose dependently by diosmin. Furthermore, diosmin could abrogate high glucose-induced apoptosis as well as JNK and P38 MAPK phosphorylation in ARPE-19 cells. Our results suggest that treatment ARPE-19 cells with diosmin halts hyperglycemia-mediated oxidative damage and thus this compound may be a candidate for preventing the visual impairment caused by DR.

Tetranortriterpenes and Limonoids from the Roots of Aphanamixis polystachya.

Phytochemical investigation of the acetone extract from the roots of Aphanamixis polystachya resulted in isolation of four new tetranortriterpenes (1-4) in addition to one protolimonoid (methyl-1ξ,7R-diacetoxy-23R,25-dihydroxy-20S,24R-21,24-epoxy-3,4-seco-apotirucall-4(28),14(15)-diene-3-oate (5)), five known limonoids (rohituka 3 (6), rohituka 7 (7), nymania 1 (8), rubrin G (9), prieurianin (10)) and a steroid (2,3-dihydroxy-5-pregnan-16-one (11)). Their structures were determined by spectroscopic analyses, including 2D-NMR (COSY, HMQC, HMBC, and NOESY) and high-resolution electrospray ionization mass spectrometry (HRESIMS). Cytotoxic and anti-inflammatory activities of these compounds were evaluated. Compounds 4 and 5 showed significant inhibition against superoxide generation and elastase release by human neutrophils in response to (formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B) (FMLP/CB).

The ethanol extract of Lonicera japonica (Japanese honeysuckle) attenuates diabetic nephropathy by inhibiting p-38 MAPK activity in streptozotocin-induced diabetic rats.

The anti-inflammatory potential of Lonicera japonica makes it an excellent source of novel medicinal targets to reduce inflammation in diabetic nephropathy. We aimed to investigate whether the ethanol extract of the flowering aerial parts of L. japonica exerts an ameliorative effect on diabetic renal inflammation using streptozotocin-induced diabetic rats. Diabetic rats were treated orally with the ethanol extract of the flowering aerial parts of L. japonica (100 and 200 mg/kg/day) for 8 weeks. The rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen, and proteinuria, along with a marked elevation in the ratio of kidney weight to body weight; all of these abnormalities were significantly reversed by the ethanol extract of the flowering aerial parts of L. japonica. The histological examinations revealed amelioration of diabetes-induced glomerular pathological changes following treatment with the ethanol extract of the flowering aerial parts of L. japonica. It reduced the accumulation of ED-1-expressing macrophages in renal tissue of diabetic rats, almost completely abolished T cell infiltration and attenuated the expression of proinflammatory cytokines. The ethanol extract of the flowering aerial parts of L. japonica downregulated the protein expression of p38 mitogen-activated protein kinase in the kidney of diabetic rats. The results suggest that it has the property to inhibit the activity of p-38 MAPK-mediated inflammatory response to halt the progression of diabetic nephropathy.

Ruscogenin protects against high-fat diet-induced nonalcoholic steatohepatitis in hamsters.

The protective effects of ruscogenin on nonalcoholic steatohepatitis in hamsters fed a high-fat diet were investigated. Ruscogenin (0.3, 1.0, or 3.0 mg/kg/day) was orally administered by gavage once daily for eight weeks. A high-fat diet induced increases in plasma levels of total cholesterol, triglycerides, and free fatty acids, while the degree of insulin resistance was lowered by ruscogenin. High-fat diet-induced hepatic steatosis and necroinflammation were improved by ruscogenin. Gene expression of inflammatory cytokines and activity of nuclear transcription factor-κB were also increased in the high-fat diet group, which were attenuted by ruscogenin. Ruscogenin decreased hepatic mRNA levels of sterol regulatory element-binding protein-1c and its lipogenic target genes. The hepatic mRNA expression of peroxisome proliferator-activated receptor α, together with its target genes responsible for fatty acid ß-oxidation were upregulated by ruscogenin. In conclusion, these findings suggest that ruscogenin may attenuate high-fat diet-induced steatohepatitis through anti-inflammatory mechanisms, reducing hepatic lipogenic gene expression, and upregulating proteins in the fatty acid oxidation process.

Polysaccharides from Liriopes Radix ameliorate streptozotocin-induced type I diabetic nephropathy via regulating NF-κB and p38 MAPK signaling pathways.

BACKGROUND: The polysaccharides from Liriopes Radix (PSLR) has been indicated to ameliorate insulin signaling transduction and glucose metabolism. We aimed to investigate whether PSLR exerts an ameliorative effect on renal damage in diabetes induced by streptozotocin. METHODS: Diabetes was induced with STZ (60 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats in the treatment group were orally dosed with PSLR (200 and 300 mg/kg/day for 8 weeks. The normal rats were chosen as nondiabetic control group. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses. RESULTS: Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight. All of these abnormalities were significantly reversed by PSLR. The histological examinations revealed amelioration of diabetes-induced glomerular pathological changes following treatment with PSLR. The less protein expressions of renal nephrin and podocin in diabetic rats were increased following treatment with PSLR. PSLR reduced the accumulation of ED-1-expressing macrophages in renal tissue of diabetic rats. PSLR almost completely abolished T cells infiltration and attenuated the expression of proinflammatory cytokines. PSLR treatments not only reduced the degradation of inhibitory kappa B kinase, but also downregulated the protein expression of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in diabetic kidney. CONCLUSIONS: The results suggest that the renal protective effects of PSLR occur through improved glycemic control and renal structural changes, which are involved in the inhibition of NF-κB and p-38 MAPK mediated inflammation.

Ruscogenin ameliorates diabetic nephropathy by its anti-inflammatory and anti-fibrotic effects in streptozotocin-induced diabetic rat.

BACKGROUND: Ruscogenin is a major steroid sapogenin in the traditional Chinese herb Ophiopogon japonicus that have multiple bioactivities. Recent studies have demonstrated that ruscogenin is involved in down-regulation of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) activation in anti-inflammatory pathways. We hypothesized that ruscogenin protects against diabetic nephropathy (DN) by inhibiting NF-κB-mediated inflammatory pathway. To test this hypothesis, the present study was to examine the effects of ruscogenin in rats with streptozotocin (STZ)-induced DN. METHODS: Diabetes was induced with STZ (60 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats in the treatment group were orally dosed with 0.3, 1.0 or 3.0 mg/kg ruscogenin for 8 weeks. The normal rats were chosen as nondiabetic control group. The rats were sacrificed 10 weeks after induction of diabetes. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses. RESULTS: Ruscogenin administration did not lower the levels of plasma glucose and glycosylated hemoglobin in STZ-diabetic rats. Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight, that were reversed by ruscogenin. Ruscogenin treatment was found to markedly improve histological architecture in the diabetic kidney. Renal NF-κB activity, as wells as protein expression and infiltration of macrophages were increased in diabetic kidneys, accompanied by an increase in protein content of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in kidney tissues. All of the above abnormalities were reversed by ruscogenin treatment, which also decreased the expression of transforming growth factor-ß1 and fibronectin in the diabetic kidneys. CONCLUSIONS: Our data demonstrated that ruscogenin suppressed the inflammation and ameliorated the structural and functional abnormalities of the diabetic kidney in rats might be associated with inhibition of NF-κB mediated inflammatory genes expression.

Seven new sesquiterpenoids from the fruits of Schisandra sphenanthera.

Fractionation of the EtOH extract from the fruits of Schisandra sphenanthera resulted in the isolation of seven new sesquiterpenoids, 1-7, in addition to the known metabolites 8-23. Among them, schiscupatetralin A (1) possesses an unprecedented structure with a CC bond between cuparenol and tetralin. The isolated new compounds were evaluated for their anti-HSV-1 and anti-inflammatory activities. The results revealed that compound 4 exhibited anti-HSV-1 activity, while compound 6 showed a significant anti-inflammatory activity.

Anti-liver fibrotic lignans from the fruits of Schisandra arisanensis and Schisandra sphenanthera.

Three new polyoxygenated C(18)-dibenzocyclooctadiene lignans, arisanschinins M and N (1 and 2) and schisphenin A (3), together with eight related metabolites (4-11), were isolated from the fruits of Schisandra arisanensis and Schisandra sphenanthera, respectively. The structures of 1-3 were elucidated on the basis of extensive spectroscopic and 2D NMR (HSQC, HMBC, and NOESY) analyses. The configuration of the biphenyl moiety in the octadiene ring was determined by circular dichroism (CD). Compound 1 possessed an unprecedented 3-(1-hydroxypropan-2-yl)-3-methyl-1,4-dioxo-2-one lactonide ring system attaching at C-6/C-14. Pharmacological studies revealed that compounds 3, 4, 6, 7, and 10 exhibited significant anti-hepatic fibrosis activity, while 9 and 11 showed cytotoxicity against HSC-T6 cells. The biogenetic pathway for compound 1 was also proposed.

Effect of topical application of chlorogenic acid on excision wound healing in rats.

This study was undertaken to evaluate the therapeutic effects of topical chlorogenic acid on excision wounds in Wistar rats. A 1 % (w/w) chlorogenic acid or silver sulfadiazine ointment was applied topically once a day for 15 days on full-thickness excision wounds created on rats. The 1 % (w/w) chlorogenic acid ointment had potent wound healing capacity as evident from the wound contraction on the 15th post-surgery day, which was similar to that produced by 1 % (w/w) silver sulfadiazine ointment. Increased rates of epithelialization were observed in the treated rats. It also improved cellular proliferation, increased tumor necrosis factor-α levels during the inflammatory phase (12 h, 24 h, 48 h, and 72 h post-wounding) of wound healing, upregulated transforming growth factor-ß1 and elevated collagen IV synthesis in the chlorogenic acid-treated group. The results also indicated that chlorogenic acid possesses potent antioxidant activity by increasing superoxide dismutase, catalase, and glutathione, and decreasing lipid peroxidation. In conclusion, these results demonstrate that topical application of chlorogenic acid can accelerate the process of excision wound healing by its ability to increase collagen synthesis through upregulation of key players such as tumor necrosis factor-α and transforming growth factor-ß1 in different phases of wound healing as well as by its antioxidant potential.

Hispidin in the Medicinal Fungus Protects Dopaminergic Neurons from JNK Activation-Regulated Mitochondrial-Dependent Apoptosis in an MPP+-Induced In Vitro Model of Parkinson's Disease.

Degenerative diseases of the brain include Parkinson's disease (PD), which is associated with moveable signs and is still incurable. Hispidin belongs to polyphenol and originates primarily from the medicinal fungi Inonotus and Phellinus, with distinct biological effects. In the study, MES23.5 cells were induced by 1-methyl-4-phenylpyridinium (MPP+) to build a cell model of PD in order to detect the protective effect of hispdin and to specify the underlying mechanism. Pretreatment of MES23.5 cells with 1 h of hispdin at appropriate concentrations, followed by incubation of 24 h with 2 µmol/L MPP+ to induce cell damage. MPP+ resulted in reactive oxygen species production that diminished cell viability and dopamine content. Mitochondrial dysfunction in MS23.5 cells exposed to MPP+ was observed, indicated by inhibition of activity in the mitochondrial respiratory chain complex I, the collapse of potential in mitochondrial transmembrane, and the liberation of mitochondrial cytochrome c. Enabling C-Jun N-terminal kinase (JNK), reducing Bcl-2/Bax, and enhancing caspase-9/caspase-3/PARP cleavage were also seen by MPP+ induction associated with increased DNA fragmentation. All of the events mentioned above associated with MPP+-mediated mitochondrial-dependent caspases cascades were attenuated under cells pretreatment with hispidin (20 µmol/L); similar results were obtained during cell pretreatment with pan-JNK inhibitor JNK-IN-8 (1 µmol/L) or JNK3 inhibitor SR3576 (25 µmol/L). The findings show that hispidin has neuroprotection against MPP+-induced mitochondrial dysfunction and cellular apoptosis and suggest that hispidin can be seen as an assist in preventing PD.

Emodin protects against high-fat diet-induced obesity via regulation of AMP-activated protein kinase pathways in white adipose tissue.

Emodin is an active herbal component traditionally used in China for treating a variety of diseases. The aim of this study was to examine the effect of emodin on the reducing lipid accumulation in white adipose tissue of high-fat diet-fed rats, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. After being fed a high-fat diet for two weeks, rats were dosed orally with emodin (20, 40, 80 mg/kg/day) or pioglitazone (20 mg/kg/day), once daily for eight weeks. Changes in body weight, feeding pattern, serum lipids, coronary artery risk index, and atherogenic index were investigated. Subcutaneous white adipose tissues were isolated for pathology histology and Western blot analyses. Changes of triglyceride accumulation in differentiated 3 T3-L1 adipocytes were also investigated. Emodin exhibited a significant concentration-dependent decrease in the intracellular accumulation of triglyceride in 3 T3-L1 adipocytes. Emodin (80 mg/kg/day) displayed similar characteristics to pioglitazone (20 mg/kg/day) in reducing body weight gain and plasma lipid levels as well as the coronary artery risk and atherogenic indices of high-fat diet-fed rats. Emodin also caused dose related reductions in epididymal white adipose tissue sizes in high-fat diet-fed rats. Emodin and pioglitazone enhanced the phosphorylation of AMP-activated protein kinase and its primary downstream targeting enzyme, acetyl-CoA carboxylase, upregulated gene expression of carnitine palmitoyl transferase 1, and downregulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the epididymal white adipose tissue of high-fat diet-fed rats. Our findings suggest that emodin could attenuate lipid accumulation in white adipose tissue through AMP-activated protein kinase activation.

Beneficial effect of traditional chinese medicinal formula danggui-shaoyao-san on advanced glycation end-product-mediated renal injury in streptozotocin-diabetic rats.

The present study was undertaken to characterize the effects of Danggui-Shaoyao-San (DSS), a famous traditional Chinese medicine formula consisting of six herbal medicines, on diabetic nephropathy. Streptozotocin-induced diabetic rats were orally administrated DSS (2.8 g kg(-1) per day) for 12 consecutive weeks. DSS partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-hour urinary albumin excretion rate, and creatinine clearance as well as the kidney hypertrophy (kidney weight/body weight ratio) and glomerular mesangial matrix expansion were ameliorated after 12 weeks of DSS treatment. The increased expression of nuclear factor-κB as well as transforming growth factor-ß(1) and the progressive accumulation of type IV collagen in kidney of diabetic rats were also attenuated by DSS. Not only the elevated levels of advanced glycation end products (AGEs) and N(ε)-(carboxymethyl)lysine but also the higher levels of lipid peroxidation products in kidney of diabetic rats were ameliorated by DSS. Decreased activity of superoxide diamutase and glutathione peroxidase in kidney of diabetic rats was enhanced by DSS. These data demonstrated that the renoprotective effects of DSS in STZ-diabetic rats not only were attributable to regulate plasma glucose to attenuate AGEs expression in diabetic glomeruli but also likely reflected its antioxidant activity.

Vinegar-Baked Radix Bupleuri Regulates Lipid Disorders via a Pathway Dependent on Peroxisome-Proliferator-Activated Receptor-α in High-Fat-Diet-Induced Obese Rats.

The aim of this study was to investigate the antiobesity and antihyperlipidemic effects of vinegar-baked Radix Bupleuri (VBRB) on high-fat diet- (HFD-) induced obese rats. After being fed HFD for two weeks, rats were dosed orally with VBRB or fenofibrate, once daily for further twelve weeks. VBRB (1.0 g kg(-1) per day) produced effects similar to fenofibrate (100 mg kg(-1)) in reducing body weight (BW) gain, visceral fat-pad weights, plasma lipid levels, as well as hepatic TG and cholesterol content of HFD-fed rats. VBRB also lowered hepatic lipid droplet accumulation and the size of epididymal adipocytes in HFD-fed rats. VBRB and fenofibrate reversed the HFD-induced downregulation of hepatic peroxisome proliferator-activated receptor (PPAR)α. HFD-induced reductions in the hepatic levels of acyl-CoA oxidase (ACO) and cytochrome P450 isoform 4A1 (CYP4A1) proteins were reversed by VBRB and fenofibrate. The elevated expression of hepatic sterol regulatory element binding proteins (SREBPs) in HFD-fed rats was lowered by VBRB and fenofibrate. The results of this study show that VBRB suppresses BW gain and body fat accumulation by increasing fatty acid oxidation, an effect which is likely mediated via upregulation of PPARα and downregulation of SREBP expression in the liver of HFD-fed rats.

Absence of Genotoxic and Mutagenic Effects of Zingiber zerumbet (L.) Smith (Zingiberaceae) Extract.

The present study evaluated the potential genotoxicity of the ethanol extracts from the rhizome of Zingiber zerumbet (L.) Smith (EEZZR) using a standard battery of tests. Chemical analysis with liquid chromatography-tandem mass spectrometry revealed that EEZZR contained Zerumbone (200.3 ± 0.37 µg/g) and 6-gingerol (102.5 ± 0.28 µg/g). There were no increases in the number of revertant colonies with EEZZR at concentrations of 150-5000 µg per plate, regardless of the metabolic activation system (S-9 mix) used in the histidine-dependent auxotrophic mutants of Salmonella typhimurium (strains TA97, TA98, TA100, TA102, and TA1535) compared to the vehicle control. Furthermore, EEZZR at doses of 150-5000 µg mL(-1) did not increase the number of structural aberrations in Chinese hamster lung cells in the presence or absence of S-9 mix. An oral administration of EEZZR to ICR mice, with doses of up to 2000 mg/kg, caused no significant increases in the number of micronucleated polychromatic erythrocytes (MNPCEs) and mean ratio of polychromatic erythrocytes to total erythrocytes. Lastly, RZZEE did not increase the incidence of MNPCEs in bone marrow. Based on these findings, it may be concluded that the use of EEZZR in traditional medicine poses no risk of genotoxicity.

Myricetin Increases Hepatic Peroxisome Proliferator-Activated Receptor α Protein Expression and Decreases Plasma Lipids and Adiposity in Rats.

The aim of this study was to investigate the antiobesity and antihyperlipidaemic effects of myricetin. Myricetin exhibited a significant concentration-dependent decrease in the intracellular accumulation of triglyceride in 3T3-L1 adipocytes. The high-fat diet (HFD)-fed rats were dosed orally with myricetin or fenofibrate, once daily for eight weeks. Myricetin (300 mg kg(-1) per day) displayed similar characteristics to fenofibrate (100 mg kg(-1) per day) in reducing lowered body weight (BW) gain, visceral fat-pad weights and plasma lipid levels of HFD-fed rats. Myricetin also reduced the hepatic triglyceride and cholesterol contents, as well as lowered hepatic lipid droplets accumulation and epididymal adipocyte size in HFD-fed rats. Myricetin and fenofibrate reversed the HFD-induced down-regulation of the hepatic peroxisome proliferator activated receptor (PPAR)α. HFD-induced decreases of the hepatic protein level of acyl-CoA oxidase and cytochrome P450 isoform 4A1 were up-regulated by myricetin and fenofibrate. The elevated expressions of hepatic sterol regulatory element binding proteins (SREBPs) of HFD-fed rats were lowered by myricetin and fenofibrate. These results suggest that myricetin suppressed BW gain and body fat accumulation by increasing the fatty acid oxidation, which was likely mediated via up-regulation of PPARα and down-regulation of SREBP expressions in the liver of HFD-fed rats.

Acute and 28-Day Subchronic Oral Toxicity of an Ethanol Extract of Zingiber zerumbet (L.) Smith in Rodents.

The objective of this study was to evaluate the acute and subacute toxicity (28 days) of the ethanol extract of Z. zerumbet rhizomes (EEZZ) via the oral route in Wistar rats of both sexes. In the acute toxicity study, Wistar rats were administered a single dose of 15 g kg(-1) of body weight by gavage, and were monitored for 14 days. EEZZ did not produce any toxic signs or deaths; the 50% lethal dose must be higher than 15 g kg(-1). In the subchronic toxicity study, EEZZ was administered by gavage at doses of 1000, 2000 and 3000 mg/kg daily for 4 weeks to Wistar rats. The subacute treatment with EEZZ did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups. Necropsy and histopathological examination, did not reveal any remarkable and treatment related changes. A no-observed adverse-effect level for EEZZ is 3000 mg kg(-1) for rats under the conditions of this study. Hence, consumption of EEZZ for various medicinal purposes is safe.

Emodin, a Naturally Occurring Anthraquinone Derivative, Ameliorates Dyslipidemia by Activating AMP-Activated Protein Kinase in High-Fat-Diet-Fed Rats.

The aim of this study was to investigate the antiobesity and antihyperlipidaemic effects of emodin on high-fat diet (HFD)-induced obese rats, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. After being fed HFD for two weeks, Wistar rats were dosed orally with emodin (40 and 80 mg kg(-1)) or pioglitazone (20 mg kg(-1)), once daily for eight weeks. Emodin (80 mg kg(-1) per day) displayed similar characteristics to pioglitazone (20 mg kg(-1) per day) in reducing body weight gain, plasma lipid levels as well as coronary artery risk index and atherogenic index of HFD-fed rats. Emodin also caused dose related reductions in the hepatic triglyceride and cholesterol contents and lowered hepatic lipid droplets accumulation in HFD-fed rats. Emodin and pioglitazone enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in hepatocytes of HFD-fed rats. Our findings suggest emodin could attenuate lipid accumulation by decreasing lipogenesis and increasing mitochondrial fatty acid ß-oxidation mediated by activation of the AMPK signaling pathway.