Lipid-lowering effects of Coffea arabica pulp aqueous extract in Caco-2 cells and hypercholesterolemic rats.

BACKGROUND: Coffea arabica pulp (CP) is the first by-product obtained from coffee berries during coffee processing. The major constituents of CP, including chlorogenic acid, caffeine, and epicatechin exhibit anti-hyperlipidemic effects in in vitro and in vivo models. Whether Coffea arabica pulp aqueous extract (CPE) has a lipid-lowering effect remains unknown. PURPOSE: This study examined the effect of CPE on cholesterol absorption, and identified the mechanisms involved in lowered cholesterol in in vitro and in vivo models. METHODS: Uptake of [3H]-cholesterol micelles and the mode of CPE inhibition were determined using human intestinal Caco-2 cells, and subsequently, confirmed using isolated rat jejunal loops. In addition, the 12-week high-fat diet-induced hypercholesterolemic rats (HF) received either CPE (1000  mg/kg BW), a sole and high dose which was selected because it contained approximately 12  mg of CGA that was previously shown to have lipid-lowering effects, or ezetimibe (10  mg/kg BW), a cholesterol inhibitor. The rats were divided into HF, HF  ++ CPE, and HF  ++ ezetimibe groups for the next 12 weeks. Normal rats received a normal diet (ND) and CPE (ND  +  CPE). Body weights and lipid profiles were evaluated. Cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), protein expression and liver X receptor alpha (LXRα) mRNA expression were determined. In vitro micellar complex properties were also investigated. RESULTS: CPE inhibited [3H]-cholesterol micelle transport in Caco-2 cells and rat jejunal loops in a dose-dependent, non-competitive manner partly by decreasing membrane NPC1L1 expression. Congruently, CPE and its major constituents activated LXRα which, in turn, down-regulated NPC1L1. Furthermore, CPE interfered with physicochemical characteristics of cholesterol mixed micelles. These data were consistent with decreased body weight and slowed body weight gain and improved lipid profiles by CPE in hypercholesterolemic rats while no change occurred in these parameters in normal rats. Down-regulated intestinal NPC1L1 expression mediated by increased LXRα mRNA were also observed in HF  ++ CPE and ND  +  CPE rats. CONCLUSION: CPE has a cholesterol-lowering effect in in vitro and in vivo via inhibition of intestinal cholesterol absorption by down-regulating NPC1L1 mediated LXRα activation and interfering with micellar complex formation. Accordingly, CPE could be developed as nutraceutical product to prevent dyslipidemia-induced obesity and insulin resistance.

Lactobacillus paracasei HII01, xylooligosaccharides, and synbiotics reduce gut disturbance in obese rats.

OBJECTIVES: The beneficial effects of pro-, pre-, and synbiotics on obesity with insulin resistance have been reported previously. However, the strain-specific effect of probiotics and the combination with various types of prebiotic fiber yield controversial outcomes and limit clinical applications. Our previous study demonstrated that the probiotic Lactobacillus paracasei (L. paracasei) HII01, prebiotic xylooligosaccharide (XOS), and synbiotics share similar efficacy in attenuating cardiac mitochondrial dysfunction in obese-insulin resistant rats. Nonetheless, the roles of HII01 and XOS on gut dysbiosis and gut inflammation under obese-insulin resistant conditions have not yet, to our knowledge, been investigated. Our hypothesis was that pro-, pre-, and synbiotics improve the metabolic parameters in obese-insulin resistant rats by reducing gut dysbiosis and gut inflammation. METHODS: Male Wistar rats were fed with either a normal or high-fat diet that contained 19.77% and 59.28% energy from fat, respectively, for 12 wk. Then, the high-fat diet rats were fed daily with a 108 colony forming unit of the probiotic HII01, 10% prebiotic XOS, and synbiotics for 12 wk. The metabolic parameters, serum lipopolysaccharide levels, fecal Firmicutes/Bacteroidetes ratios, levels of Enterobacteriaceae, Bifidobacteria, and gut proinflammatory cytokine gene expression were quantified. RESULTS: The consumption of probiotic L. paracasei HII01, prebiotic XOS, and synbiotics for 12 wk led to a decrease in metabolic endotoxemia, gut dysbiosis (a reduction in the Firmicutes/Bacteroidetes ratio and Enterobacteriaceae), and gut inflammation in obese-insulin resistant rats. CONCLUSIONS: Pro-, pre-, and synbiotics reduced gut dysbiosis and gut inflammation, which lead to improvements in metabolic dysfunction in obese-insulin resistant rats.

Anthocyanin-rich Riceberry bran extract attenuates gentamicin-induced hepatotoxicity by reducing oxidative stress, inflammation and apoptosis in rats.

Liver plays an important role in the detoxification and metabolic elimination of various drugs and harmful substances. The damaging effects on the liver tissue treated with gentamicin are multi-factorial and their mechanisms remain unclear. This study aimed to investigate the possible protective effects of anthocyanin-rich Riceberry bran extract on gentamicin-induced hepatotoxicity in rats. Riceberry bran extract was given by oral administration 30min before gentamicin injection for 15 consecutive days. Serum levels of liver marker enzymes, AST and ALT, were significantly elevated and the total serum protein level was markedly reduced in gentamicin-treated rats. Gentamicin injection led to the significant increase in hepatic MDA level and decrease SOD expression. Liver inflammation and apoptosis were observed in gentamicin-treated rats as indicated by the increases in NF-κB, TNF-αR1, COX2, and iNOS, caspase-3, Bax, and decrease in Bcl-XL expressions. Riceberry bran extract significantly prevented gentamicin-induced the elevations of serum AST, ALT and the reduction of serum total protein. These were related to the inhibition of oxidative stress, inflammation and apoptosis in Riceberry bran extract treatment. These findings suggest that anthocyanin-rich Riceberry bran extract can prevent liver dysfunction and damage induced by gentamicin, possibly through its antioxidant, anti-inflammatory and anti-apoptotic effects.

Riceberry bran extract prevents renal dysfunction and impaired renal organic anion transporter 3 (Oat3) function by modulating the PKC/Nrf2 pathway in gentamicin-induced nephrotoxicity in rats.

PURPOSE: This study investigated the protective effects of Riceberry bran extract (RBBE) on renal function, and the function and expression of renal organic anion transporter 3 (Oat3) in gentamicin-induced nephrotoxicity in rats and explored the mechanisms for its protective effects. MATERIAL AND METHODS: Male Sprague Dawley rats (n= 42) were divided into six groups to receive normal saline, gentamicin (100mg/kg), co-treatment of gentamicin and RBBE (at dose of 250, 500 and 1000mg/kg), and RBBE (at dose of 1000mg/kg) only, for consecutive fifteen days. Renal function, oxidative and antioxidative markers, the function and expression of Oat3 and histological changes in the kidney were evaluated. RESULTS: Elevation of BUN, serum creatinine levels and reduction in urine creatinine and creatinine clearance indicated decreased renal function in the gentamicin-treated rats. The decrease of [3H]ES uptake in the renal cortical slices of these rats, reflecting the attenuation of Oat3 transport function that was accompanied by decreased expression of Oat3. Moreover, increased MDA level and reduced superoxide dismutase (SOD) and glutathione (GSH) activities were found in gentamicin-treated rats compared to the control group. These changes were associated with the upregulated PKCα, Nrf-2, Keap 1, NQO-1 and HO-1 expressions in kidneys. RBBE treatment improved the renal function and Oat3 transport function and expression in gentamicin-treated rats. The oxidative status was also restored by RBBE treatment. CONCLUSION: RBBE protects kidney injury by its antioxidant effect, subsequently leading to modulation of the PKC/Nrf2 antioxidant defense pathway.

Pinocembrin attenuates gentamicin-induced nephrotoxicity in rats.

Oxidative stress mediated apoptosis of renal tubular cells is a major pathology of gentamicin-induced nephrotoxicity, which is one of the prevailing causes of acute renal failure. Pinocembrin is a major flavonoid found in rhizomes of fingerroot (Boesenbergia pandurata). It has pharmacological and biological activities including antimicrobial, anti-inflammatory, and antioxidant effects. Preclinical studies have suggested that pinocembrin protects rat brain and heart against oxidation and apoptosis induced by ischemia-reperfusion. The aim of the current study was to investigate the mechanisms of renoprotection elicited by pinocembrin in gentamicin-induced nephrotoxicity. Nephrotoxicity was induced in rats by intraperitoneal injection (i.p.) of gentamicin, and pinocembrin was administered via i.p. 30 min before gentamicin treatment for 10 days. Gentamicin-induced nephrotoxicity was indicated by the reduced renal function and renal Oat3 function and expression. Gentamicin treatment also stimulated Nrf2, HO-1, and NQO1, as well as the pro-apoptotic proteins Bax and caspase-3, concomitant with the attenuation of Bcl-XL expression in the renal cortical tissues. Pinocembrin pretreatment improved renal function and renal Oat3 function and reduced oxidative stress and apoptotic conditions. These findings indicate that pinocembrin has a protective effect against gentamicin-induced nephrotoxicity, which may be due in part to its antioxidant and anti-apoptotic effects, subsequently leading to improved renal function.

Antidiabetic and renoprotective effects of Cladophora glomerata Kützing extract in experimental type 2 diabetic rats: a potential nutraceutical product for diabetic nephropathy.

Cladophora glomerata extract (CGE) has been shown to exhibit antigastric ulcer, anti-inflammatory, analgesic, hypotensive, and antioxidant activities. The present study investigated antidiabetic and renoprotective effects of CGE in type 2 diabetes mellitus (T2DM) rats. The rats were induced by high-fat diet and streptozotocin and supplemented daily with 1 g/kg BW of CGE for 12 weeks. The renal transport function was assessed by the uptake of para-aminohippurate mediated organic anion transporters 1 (Oat1) and 3 (Oat3), using renal cortical slices. These two transporters were known to be upregulated by insulin and PKCζ while they were downregulated by PKCα activation. Compared to T2DM, CGE supplemented rats had significantly improved hyperglycaemia, hypertriglyceridemia, insulin resistance, and renal morphology. The baseline uptake of para-aminohippurate was not different among experimental groups and was correlated with Oat1 and 3 mRNA expressions. Nevertheless, while insulin-stimulated Oat1 and 3 functions in renal slices were blunted in T2DM rats, they were improved by CGE supplementation. The mechanism of CGE-restored insulin-stimulated Oat1 and 3 functions was clearly shown to be associated with upregulated PKCζ and downregulated PKCα expressions and activations. These findings indicate that CGE has antidiabetic effect and suggest it may prevent diabetic nephropathy through PKCs in a T2DM rat model.

Antioxidant and renoprotective effects of Spirogyra neglecta (Hassall) Kützing extract in experimental type 2 diabetic rats.

Spirogyra neglecta extract (SNE) has shown antihyperglycemia and antihyperlipidemia in type 2 diabetic mellitus (T2DM) rats. This study investigated the antioxidant and renoprotective effects of SNE in T2DM rats induced by high-fat diet with low-single dose streptozotocin. T2DM rats were fed daily with SNE (0.25, 0.5, and 1 g/kg BW) for 12 weeks. Renal morphology, malondialdehyde levels, qPCR, and western blotting were analyzed. Renal cortical slices were used to determine renal transport of organic anions, which are estrone sulfate and para-aminohippurate, mediated through organic anion transporter 3-Oat3. Insulin and PKCζ were known to activate Oat3 function while it was inhibited by PKCα. Compared to T2DM, plasma glucose, triglyceride, insulin resistance, renal morphology, and malondialdehyde levels were significantly improved by SNE supplementation. Reduced glutathione peroxidase and nuclear factor κB expressions were related to antioxidant effect of SNE. Oat3 mRNA and protein were not different among groups, but insulin-stimulated rOat3 followed by anion uptakes was abolished in T2DM. This was restored in the slices from SNE treatment. The mechanism of SNE-improved Oat3 was associated with PKCα and PKCζ expressions and activities. These findings indicate that SNE has beneficial effects on renal transport through antioxidant enzymes and PKCs in T2DM rats.

Reversible acetylcholinesterase inhibitory effect of Tabernaemontana divaricata extract on synaptic transmission in rat CA1 hippocampus.

BACKGROUND & OBJECTIVES: Acetylcholinesterase inhibitors (AChE-Is) are used for the treatment of Alzheimer's disease (AD). These drugs including galanthamine have been shown to modulate synaptic activity in hippocampus and improve memory processes. Although Tabernaemontana divaricata extract (TDE) has been used as traditional medicine for various pharmacological effects, its effect in enhancing cholinergic activity provides additional benefit to its known effects. We investigated whether TDE can modulate the synaptic function in hippocampus and compared its effects to those of galanthamine. METHODS: Hippocampal slices were prepared from male wistar rats, functional effects of TDE were characterized by using pharmacological tools and extracellular recordings of field excitatory postsynaptic potentials (fEPSPs). RESULTS: TDE significantly reduced fEPSPs. The fEPSPs reduction was prevented by atropine, but not pancuronium. These TDE effects were similar to those of galanthamine. INTERPRETATION & CONCLUSIONS: Our findings indicate that TDE can effectively modulate synaptic responses in the hippocampus similar to galanthamine, suggesting that this traditional medicine could be beneficial in ageing with ACh deprivation in the brain.

Effects of curcuminoid supplement on cardiac autonomic status in high-fat-induced obese rats.

OBJECTIVE: Sudden cardiac death in obesity is frequently associated with sympathetic activation due to an elevated plasma free-fatty acid (FFA) level. Curcuminoids, the phenolic yellowish pigments of turmeric, display antioxidative and lipid-lowering activities. We hypothesized that curcuminoids ameliorate cardiac sympathovagal disturbance in high-fat-induced obese rats. METHODS: Male Wistar rats were divided into five groups. A normal-diet control (NDC) group received a normal-fat diet (12% calories as fat) and a high-fat-diet control (HDC) group received a high-fat diet (60% calories as fat) for 12 wk. Three other groups received high-fat diets with curcuminoid supplement at concentrations of 30mg (HD(30)), 60mg (HD(60)), and 90mg (HD(90)) per kilogram of body weight every day for 12 wk. Heart rate variability was determined to assess cardiac autonomic status at weeks 0 and 12. RESULTS: Body weight, visceral fat mass, plasma FFA, and glucose levels increased significantly in the HDC group compared with the NDC group. Low frequency power in normalized units (LFnu) and the ratio of LF to high-frequency power (HF) in the HDC group were significantly higher, whereas HFnu in the HDC group was significantly lower than in the NDC group. Plasma FFA levels correlated significantly with LFnu and LF/HF ratio. Compared with the HDC group, plasma FFA, glucose levels, LFnu, and LF/HF ratio were significantly decreased in the HF(30), HF(60), and HF(90) groups. CONCLUSION: Elevated plasma FFA in high-fat-induced obese rats is associated with an increased LF/HF ratio, an expression of sympathovagal disturbance. Curcuminoid supplementation ameliorates cardiac autonomic imbalance in high-fat-fed rats, probably due to its lipid-lowering effect.

Ethnobotany & ethnopharmacology of Tabernaemontana divaricata.

Tabernaemontana divaricata a common garden plant in tropical countries has been used as a traditional medicine. However, no recent review articles of T. divaricata, particularly discussing its pharmacological properties, are available. This review presents the ethnobotany and ethnopharmacology of T. divaricata as well as its potential therapeutic benefits especially of the alkaloidal and non-alkaloidal constituents. Included, are the characteristics of 66 alkaloids isolated and identified from T. divaricata. Non-alkaloids including the enzymes, pyrolytic oil, hydrocarbons, terpenoid and phenolic acids are also documented. Chemotaxonomic aspects of each alkaloid as well as information regarding the pharmacology of crude extracts and individual alkaloids from T. divaricata have been assembled and appraised. The beneficial properties of T. divaricata are antioxidant, anti-infection, anti-tumour action, analgesia and the enhancement of cholinergic activity in both peripheral and central nervous systems. The augmentation of cholinergic function may be of therapeutic benefit for many neurodegenerative diseases, particularly myasthenia gravis and Alzheimer's disease.