Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer.

As a phenolic acid compound, caffeic acid (CA) can be isolated from different sources such as tea, wine and coffee. Caffeic acid phenethyl ester (CAPE) is naturally occurring derivative of CA isolated from propolis. This medicinal plant is well-known due to its significant therapeutic impact including its effectiveness as hepatoprotective, neuroprotective and anti-diabetic agent. Among them, anti-tumor activity of CA has attracted much attention, and this potential has been confirmed both in vitro and in vivo. CA can induce apoptosis in cancer cells via enhancing ROS levels and impairing mitochondrial function. Molecular pathways such as PI3K/Akt and AMPK with role in cancer progression, are affected by CA and its derivatives in cancer therapy. CA is advantageous in reducing aggressive behavior of tumors via suppressing metastasis by inhibiting epithelial-to-mesenchymal transition mechanism. Noteworthy, CA and CAPE can promote response of cancer cells to chemotherapy, and sensitize them to chemotherapy-mediated cell death. In order to improve capacity of CA and CAPE in cancer suppression, it has been co-administered with other anti-tumor compounds such as gallic acid and p-coumaric acid. Due to its poor bioavailability, nanocarriers have been developed for enhancing its ability in cancer suppression. These issues have been discussed in the present review with a focus on molecular pathways to pave the way for rapid translation of CA for clinical use.

Danggui Buxue decoction ameliorates lipid metabolic defects involved in the initiation of diabetic atherosclerosis; identification of active compounds.

OBJECTIVE: To determine the constituent compounds of Danggui buxue decoction (DBD) involved and the potential mechanisms mediating its effects, with specific reference to lipids playing a role in the initiation of diabetic atherosclerosis. METHODS: Liquid chromatography-tandem mass spectrometry was used to identify and quantify the absorbed bioactive compounds (ABCs) present in DBD. Goto-Kakizaki (GK) rats were randomly allocated to a diabetes atherosclerosis (DA) group, a DBD group, and an ABC group (10 per group), which were all high-fat diet-fed. The treated rats were administered DBD (4 g/kg) or ABCs (in amounts equal to those present in DBD) once daily for 28 d, and a control group of Wistar rats were administered vehicle. Body mass gain, fasting blood glucose, and homeostasis assessment of insulin resistance (HOMA- IR) were measured. Serum triglyceride (TG), cholesterol (CHOL), high density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL- C) and tumor necrosis factor-α (TNF-α) concentrations were determined. Hematoxylin and eosin staining and microscopy were used to characterize the abdominal aorta and the expression of lipogenic genes was quantified in this vessel. RESULTS: Seven ABCs were identified in rat serum: ferulic acid, formononetin, calycosin, astragaloside, caffeic acid, ligustilide, and butyphthalide. DBD significantly reduced HOMA-IR, the serum concentrations of TG, CHOL, and LDL-C, and the expression of the lipogenic genes monocyte chemotactic protein 1, Fas, intercellular adhesion molecule 1, and Cd36 in aorta; and significantly increased the mRNA expression of Scd1 in aorta. CONCLUSION: DBD affects lipid metabolism in the early stage of atherosclerosis in diabetic GK rats, with the mechanism likely involving the regulation of lipid metabolic genes in vessels. The contribution of ABCs to the effect of DBD on lipid metabolism was 24%-101%.

High cholesterol diet promotes dysfunction of arginase and cholinergic enzymatic system in rats: ameliorative role of caffeic and chlorogenic acids.

BACKGROUND: Dietary phenolic compounds intake have been reported to have an inverse relationship to the prevalence of hypercholesterolemia. The objective of this study is to determine the effect of caffeic acid (CFA) and chlorogenic acid (CGA) on rats fed with high cholesterol diet (HCD). METHODS: Experimental animals were fed with high cholesterol diet (HCD) for a period of 21 days while simvastatin (0.2 mg/kg BWT), CFA and CGA (10 and 15 mg/kg BWT) were administered daily. RESULTS: Activity of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and arginase were significantly (P<0.05) higher in the rats fed with HCD alone. Also, level of malondiadehyde equivalent compounds (MDA) was significantly (P<0.05) elevated in hypercholesterolemic rats. Nevertheless, treatment with simvastatin, CFA and CGA normalized altered AChE, BChE and arginase activities as well as improved antioxidant status in hypercholesterolemic rats. CONCLUSION: CFA and CGA could offer protective role in hypercholeseterolemic rats via their antioxidant potentials as well as restoring altered activity of acetylcholinesterase, butrylcholinesterase and arginase. Based on our findings chlorogenic acid exhibits better attribute.

UFLC-MS/MS Determination and Population Pharmacokinetic Study of Tanshinol, Ginsenoside Rb1 and Rg1 in Rat Plasma After Oral Administration of Compound Danshen Dripping Pills.

BACKGROUND AND OBJECTIVES: As a traditional Chinese Materia Medica (CMM), the Compound Danshen Dripping Pill (CDDP) is widely used for the treatments of cardiovascular diseases. In view of its undefined applicable population and dosage, a population pharmacokinetic (PPK) study is required. The objective of this study was to explore the feasibility of multi-component CMM PPK in rat plasma after oral administration of CDDP based on sparse sampling. METHODS: In this research, a simple, rapid and highly sensitive UFLC-MS/MS method for the simultaneous determination of tanshinol (TSL), ginsenoside Rb1 (GRb1) and ginsenoside Rg1 (GRg1) has been successfully developed in rat plasma. Moreover, the validated method has been applied to a PPK study of CDDP based on sparse data. We established the PPK models for these three main active constituents using a nonlinear mixed-effects model, taking into account of factors such as gender, age in weeks and weight. RESULTS: The PPK models of TSL and GRb1 were best described by a one-compartment model with linear elimination and first-order absorption. The model of GRg1 was best described by a two-compartment model with first-order absorption. Bootstrap validation and a visual predictive check confirmed the predictive ability, the model stability and the precision of the parameter estimates from these models. CONCLUSION: As a preliminary exploration toward the clinical population pharmacokinetic research, this study provides a reference for the population pharmacokinetic study of traditional CMM.

Tanshinol A Ameliorates Triton-1339W-Induced Hyperlipidemia and Liver Injury in C57BL/6J Mice by Regulating mRNA Expression of Lipemic-Oxidative Injury Genes.

Tanshinol A, which is derived from a traditional Chinese herbal Radix Salviae Miltiorrhizae is indicative of a hypolipidemic candidate. Therefore, we aim to validate its hypolipidemic activity of tanshinol A and explore its mechanism in triton-1339W-induced hyperlipidemic mice model, which possess multiply pathogenesis for endogenous lipid metabolism disorder. Experimental hyperlipidemia mice are treated with or without tanshinol A (i.g. 40, 20, 10 mg/kg), and blood and liver tissue were collected for validating its hypolipidemic and hepatic protective effect, and hepatic mRNA expression profile, which was associated with lipid metabolism dysfunction and liver injury, was detected by RT-qPCR. As results show, triton-1339W-induced abnormal of serum TC, TAG, HDL-C, LDL-C, SOD, MDA, GOT, and GPT is remarkably attenuated by tanshinol A. In pathological experiment, triton-1339W-induced hepatocellular ballooning degeneration, irregular central vein congestion, and inflammation infiltration are alleviated by tanshinol A. Correspondingly, hepatic mRNA expression of Atf4, Fgf21, Vldlr, Nqo1, Pdk4, and Angptl4, which are genes regulating lipemic-oxidative injury, are significantly increased by tanshinol A by 2~6 fold. Abcg5, Cd36, and Apob, which are responsible for cholesterol metabolism, are mildly upregulated. Noticeably, triton-1339W-suppressed expressions of Ptgs2/Il10, which are genes responsible for acute inflammation resolution in liver injury, are remarkably increased by tanshinol A. Conclusively, tanshinol A exerted hypolipidemic effect and hepatoprotective effect through restoring triton-1339W-suppressed mRNA expression, which may be involved in Atf4/Fgf21/Vldlr and Ptgs2/Il-10 signaling pathways.

Quantitative determination of characteristic components from compound of Lysionotus pauciflorus Maxim. by LC-MS/MS and its application to a pharmacokinetic study.

Tuberculosis of cervical lymph nodes is called scrofula in Traditional Chinese Medicine (TCM). Clinical manifestation is that unilateral or bilateral neck can have multiple enlarged lymph nodes of different sizes. Current therapeutic drugs include Lysionotus pauciflorus Maxim. tablets and compound of Lysionotus pauciflorus Maxim., which have a significant effect on tuberculosis of cervical lymph nodes. This compound is composed of three herbs, Lysionotus pauciflorus Maxim., Prunella vulgaris L. and Artemisia argyi Levl.et Vant. A selective and sensitive LC-MS/MS method was established and validated in rat plasma for the first time. Chromatographic separation was achieved on a Wonda Cract ODS-2 C18 Column (150 mm × 4.6 mm, 5 µm). The mobile phase contained 0.1% formic acid aqueous solution and acetonitrile with a flow rate of 0.8 mL/min. The detection was performed in negative electrospray ionization mode and the precursor/product ion transitions of six components and internal standard (IS) sulfamethoxazole were quantified in multiple reaction monitoring (MRM) using QTRAP-3200 MS/MS. The method fulfilled US Food and Drug Administration guidelines for selectivity, sensitivity, accuracy, precision, matrix effect, extraction recovery, dilution integrity, and stability. This proposed method was then successfully applied to a pharmacokinetic study after oral administration of 10 mL/kg compound extracts in rats. The pharmacokinetic parameters and plasma concentration-time profiles would prove valuable in pre-clinical and clinical investigations on the disposition of compound medicine.

Effects of Enteric Environmental Modification by Coffee Components on Neurodegeneration in Rotenone-Treated Mice.

Epidemiological studies have shown that coffee consumption decreases the risk of Parkinson's disease (PD). Caffeic acid (CA) and chlorogenic acid (CGA) are coffee components that have antioxidative properties. Rotenone, a mitochondrial complex I inhibitor, has been used to develop parkinsonian models, because the toxin induces PD-like pathology. Here, we examined the neuroprotective effects of CA and CGA against the rotenone-induced degeneration of central dopaminergic and peripheral enteric neurons. Male C57BL/6J mice were chronically administered rotenone (2.5 mg/kg/day), subcutaneously for four weeks. The animals were orally administered CA or CGA daily for 1 week before rotenone exposure and during the four weeks of rotenone treatment. Administrations of CA or CGA prevented rotenone-induced neurodegeneration of both nigral dopaminergic and intestinal enteric neurons. CA and CGA upregulated the antioxidative molecules, metallothionein (MT)-1,2, in striatal astrocytes of rotenone-injected mice. Primary cultured mesencephalic or enteric cells were pretreated with CA or CGA for 24 h, and then further co-treated with a low dose of rotenone (1⁻5 nM) for 48 h. The neuroprotective effects and MT upregulation induced by CA and CGA in vivo were reproduced in cultured cells. Our data indicated that intake of coffee components, CA and CGA, enhanced the antioxidative properties of glial cells and prevents rotenone-induced neurodegeneration in both the brain and myenteric plexus.

Effects of dietary caffeic acid supplement on antioxidant, immunological and liver gene expression responses, and resistance of Nile tilapia, Oreochromis niloticus to Aeromonas veronii.

The present study investigated the effects of dietary caffeic acid on haematological, serum biochemical, non-specific immune and liver gene expression responses of Nile tilapia, Oreochromis niloticus. Five experimental groups of fish with mean weights of 89.85 ±â€¯2.5 g were used in the study; three of them were fed with caffeic acid incorporated diets (1 g kg-1-Caf1, 5 g kg-1-Caf5, 10 g kg-1-Caf10), whereas an additive free basal diet served as the control. Additionally, the fifth group was an antibiotic medicated diet (0.02 g kg-1-AMF), prepared with the florfenicol. Dietary caffeic acid especially at 5 g kg-1 significantly increased phagocytic index, potential killing activity, respiratory burst activity, serum myeloperoxidase activity and serum catalase activity. Furthermore, increased levels of immune expression [heat shock protein 70 (HSP70), interleukin 1, beta (IL-1ß), tumor necrosis factor (TNF-α), CC-chemokine (CC1), interleukin 8 (IL-8), toll-like receptor 7 (tlr-7), interferon gamma (IFN-γ) and immunoglobulin M (IgM)] and antioxidant related genes [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] in the liver of fish fed with 5 g kg-1 caffeic acid. At the end of the 20-day challenge period the survival rates were significantly higher in the Caf5 and AMF groups compared to all other treatment groups. As a result, feeding Nile tilapia with a diet containing 5 g kg-1 caffeic acid over a period of 60 days might be adequate to improve fish immune parameters, antioxidant status, as well as survival rate against A. veronii, similar to antibiotic treatment. Thus caffeic acid can be suggested as a dietary substitute for antibiotic to prevent A. veronii in tilapia.

Identification of poliumoside metabolites in rat plasma, urine, bile, and intestinal bacteria with UPLC/Q-TOF-MS.

Poliumoside is representative of phenylethanoid glycosides, which are widely found in many plants. Poliumoside is also regarded as the main active component of Callicarpa kwangtungensis Chun (CK), though its oral bioavailability in rat is extremely low (0.69%) and its in vivo and in vitro metabolism has not yet been systematically investigated. In the present study, an ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) method was employed to identify the metabolites and investigate the metabolic pathways of poliumoside in rat after oral administration 1.5 g·kg-1 of poliumoside. As a result, a total of 34 metabolites (30 from urine, 17 from plasma, and 4 from bile) and 9 possible metabolic pathways (rearrangment, reduction, hydration, hydrolyzation, dehydration, methylation, hydroxylation, acetylation, and sulfation) were proposed in vivo. The main metabolite, acteoside, was quantified after incubated with rat intestinal bacteria in vitro. In conclusion, the present study systematically explored the metabolites of poliumoside in vivo and in vitro, proposing metabolic pathways that may be significant for further metabolic studies of poliumoside.

Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation.

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg-1. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.

In-vivo metabolite profiling of chicoric acid in rat plasma, urine and feces after oral administration using liquid chromatography quadrupole time of flight mass spectrometry.

Chicoric acid (CA) is an active derivative of caffeic acid, which is naturally present in many medicinal plants and vegetables. In the present study, the metabolic profile of CA was determined in rat plasma, urine and feces and was subsequently used to propose the metabolic pathways of CA. CA (100 mg/kg) was orally administered to rats by gastric intubation. Then, the plasma, urine and feces samples were collected and treated with methanol and acetonitrile (1:1, V/V) to precipitate the proteins. The pretreated samples were separated by ultra performance liquid chromatography (UPLC) equipped with an HSS T3 column (2.1 mm × 100 mm I.D., 1.7 µm) and with quadrupole time-of-flight mass spectrometry (Q-TOF-MS) as the detection method. A total of nineteen metabolites were detected and identified based on the characteristics of their deprotonated ions in the plasma, urine and feces samples. The results revealed that the metabolism of CA followed a number of known in-vivo mammalian biotransformation pathways including hydrolysis, reduction, methylation, sulfation, glucuronidation, acetylation, isomerization and deoxygenation.

Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice.

Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.

The effects of pollen, propolis, and caffeic acid phenethyl ester on tyrosine hydroxylase activity and total RNA levels in hypertensive rats caused by nitric oxide synthase inhibition: experimental, docking and molecular dynamic studies.

The objective of the present study was to evaluate the effects of propolis, pollen, and caffeic acid phenethyl ester (CAPE) on tyrosine hydroxylase (TH) activity and total RNA levels of Nω-nitro-L-arginine methyl ester (L-NAME) inhibition of nitric oxide synthase in the heart, adrenal medulla, and hypothalamus of hypertensive male Sprague dawley rats. The TH activity in the adrenal medulla, heart, and hypothalamus of the rats was significantly increased in the L-NAME group vs. control (p < 0.05). Treatment with L-NAME led to a significant increase in blood pressure (BP) in the L-NAME group compared to control (p < 0.05). These data suggest that propolis, pollen, and CAPE may mediate diminished TH activity in the heart, adrenal medulla, and hypothalamus in hypertensive rats. The decreased TH activity may be due to the modulation and synthesis of catecholamines and BP effects. In addition, the binding mechanism of CAPE within the catalytic domain of TH was investigated by means of molecular modeling approaches. These data suggest that the amino acid residues, Glu429 and Ser354 of TH may play a pivotal role in the stabilization of CAPE within the active site as evaluated by molecular dynamics (MD) simulations. Gibbs binding free energy (ΔGbinding) of CAPE in complex with TH was also determined by post-processing MD analysis approaches (i.e. Poisson-Boltzmann Surface Area (MM-PBSA) method).

Modulatory effect of caffeic acid on cholinesterases inhibitory properties of donepezil.

Background Donepezil hydrochloride commonly used in the management of Alzheimer's disease (AD), exhibiting its inhibitory effects on acetylcholinesterase and butyrylcholinesterase activity thereby enhance cognitive function. Caffeic acid member of hydroxycinnamic acid is widely present in human diet. This study aims to investigate influence of caffeic acid on acetylcholinesterase and butyrylcholinesterase inhibitory properties of donepezil (in vitro). Methods 5 mg of donepezil was dissolved in 50 mL distilled water while 10 mg of caffeic acid was dissolved in 100 mL distilled water. Therefore, mixtures of samples were prepared as follows: A2=donepezil 0.075 mg/mL+caffeic acid 0.025 mg/mL; A3=donepezil 0.050 mg/mL+caffeic acid 0.050 mg/mL; A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL. All samples were kept in the refrigerator at 4 °C for subsequent analysis. Results The result showed that all the combinations show an inhibitory effect on acetylcholinesterase and butyrylcholinesterase activity in vitro, with the combination A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL had significant (p<0.05) highest inhibitory effect on acetylcholinesterase and butyrylcholinesterase activity in vitro. More so, all the samples were able to prevent pro-oxidants (FeSO4 and sodium nitroprusside [SNP] ) induced lipid peroxidation in rat brain homogenate, with the combination A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL and A3=donepezil 0.050 mg/mL+caffeic acid 0.050 mg/mL had highest inhibitory effect against FeSO4 and SNP induced lipid peroxidation in rat brain homogenate in vitro respectively. Moreover, all the samples exhibit antioxidant properties as typified by their ability to chelate iron (II) ion (Fe2+), hydroxyl radical (OHÙ­) radical scavenging ability and ferric reducing property (FRAP). Conclusions Therefore, the combination of caffeic acid with donepezil enhances the antioxidant properties of donepezil. The combination of caffeic acid with donepezil could be a therapeutic aid in the management of AD, possibly with fewer side effects of donepezil. Nevertheless, the combination donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL acid look promising.

Immunosuppressive effect of extracts from leaves of Fraxinus Mandshurica Rupr.

Plants provide a rich resource of medicinal material for research and development of new medicine. To discover new compounds as Immunosuppressant from plants, we evaluated the immunosuppressive effect of different fractions and particularly one compound (Calceolarioside A) that were extracted from the leaves of Fraxinus Mandshurica Rupr. The fractions and the compound were tested on the ability to reduce Immunoglobulin E (IgE) secretion by human U266 multiple myeloma cells (U266 cells) and to reduce interleukin-2 (IL-2) secretion by mouse spleen cells. Our results showed that both the butanol extract fraction and the compound of Calceolarioside A inhibited the IgE and IL-2 production in U266 cells and mouse spleen cells respectively, and no cytotoxicity was observed within the effective dose range. These results suggest that Calceolarioside A could potentially serve as an immunosuppressant.

Study on the small intestine absorptive kinetics characters of tanshinol and protocatechualdehyde of Salvia miltiorrhiza extracts in rats in vivo.

In order to provide scientific basis for clinical selection of drugs, to compare and analyze the effective constitutes and the intestinal absorption in vivo in rats of the compound salvia tablets and compound salvia dropping pills (taken as the representatives). Determine the contents of tanshinol, protocatechuic aldehyde, salvianolic acid B and tanshinone II A, cryptotanshinone, ginseng saponin Rg1 and Rb1 in the compound salvia tablets and compound salvia dropping pills by High Performance Liquid Chromatography (HPLC). The intestinal absorption condition of the tanshinol, protocatechuic aldehyde, salvianolic acid B of the compound salvia tablets and compound salvia dropping pills in rats were detected by intestinal perfusion experiment. Only the intake of protocatechuic aldehyde in the compound salvia tablets was higher than in the compound dropping pills, the intake of the other 6 effective constitutes were all lower than in the compound dropping pills. The intestinal absorption of protocatechuic aldehyde was rather complete, while the intestinal absorption of tanshinol and salvianolic acid B were not significant. The duodenum was the main absorption region of these three components. The absorption of protocatechuic aldehyde was different in different regions of the intestines. Each intake of the effective constitutes in the tablets and dropping pills were significantly different, and the rat intestinal absorption of part of the components were different.

Caffeic acid, morin hydrate and quercetin partially attenuate sulfur mustard-induced cell death by inhibiting the lipoxygenase pathway.

Sulfur mustard (SM) is an alkylating agent, which has been used as in chemical warfare in a number of conflicts. As the generation of reactive oxygen species (ROS), and adducts in DNA and proteins have been suggested as the mechanism underlying SM­induced cytotoxicity, the present study screened several antioxidant candidates, including tannic acid, deferoxamine mesylate, trolox, vitamin C, ellagic acid and caffeic acid (CA) to assess their potential as therapeutic agents for SM­induced cell death. Among several antioxidants, CA partially alleviated SM­induced cell death in a dose­dependent manner. Although CA treatment decreased the phosphorylation of p38 mitogen­activated protein (MAP) kinase and p53, p38 MAP kinase inhibition by SB203580 did not affect SM­induced cell death. As CA has also been reported as a 15­lipoxygenase (15­LOX) inhibitor, the role of 15­LOX in SM­induced cytotoxicity was also examined. Similar to the results observed with CA, treatment with PD146176, a specific 15­LOX inhibitor, decreased SM­induced cytotoxicity, accompanied by decreases in the production of tumor necrosis factor­α and 15­hydroxyeicosatetraenoic acid. Furthermore, the present study investigated the protective effects of two natural 15­LOX inhibitors, morin hydrate and quercetin, in SM­induced cytotoxicity. As expected, these inhibitors had similar protective effects against SM­induced cytotoxicity. These antioxidants also reduced the generation of ROS and nitrate/nitrite. Therefore, the results of the present study indicated that the natural products, CA, quercetin and morin hydrate, offer potential as adjuvant therapeutic agents for SM­induced toxicity, not only by reducing inflammation mediated by the p38 and LOX signaling pathways, but also by decreasing the generation of ROS and nitrate/nitrite.

Protective Effects of Intralipid and Caffeic Acid Phenethyl Ester (CAPE) on Hepatotoxicity and Pancreatic Injury Caused by Dichlorvos in Rats.

The present study was aimed to the investigate the protective effects of caffeic acid phenethyl ester (CAPE) and intralipid (IL) on hepatotoxicity and pancreatic injury caused by acute dichlorvos (D) intoxication in rats. Forty-eight Wistar rats were randomly divided into seven groups each containing seven rats except control groups. The groups included control, D, CAPE, IL, D + CAPE, D + IL, and D + CAPE + IL. Total antioxidant status and total oxidative stress levels were measured by automated colorimetric assay. Tissues were evaluated using hematoxylin and eosin (H&E) staining. Tissues were analyzed with hematoxylin and eosin by using standard protocols. Also, Bcl-2, Bax and caspase-3 were evaluated by immunohistochemical method in liver tissue. Total oxidant status in control, CAPE, and IL groups were significantly lower, and total antioxidant status in the D + CAPE, D + IL, and D + IL + CAPE groups were significantly higher compared to the D group. CAPE and IL treatment decreased the apoptotic and mitotic cell count in liver tissue. Parenchymal necrosis caused by dichlorvos is observed in pancreas tissues of rats. Mild congestion and edema formation occurred in pancreas tissues following D + CAPE and D + IL therapies. These results indicate that CAPE and IL have the potential to decrease oxidative stress and hepatic and pancreatic injuries caused by acute dichlorvos intoxication. These drugs can be considered as a new method for supportive and protective therapy against pesticide intoxication.

Coffee Consumption Increases the Antioxidant Capacity of Plasma and Has No Effect on the Lipid Profile or Vascular Function in Healthy Adults in a Randomized Controlled Trial.

BACKGROUND: Coffee, a source of antioxidants, has controversial effects on cardiovascular health. OBJECTIVE: We evaluated the bioavailability of chlorogenic acids (CGAs) in 2 coffees and the effects of their consumption on the plasma antioxidant capacity (AC), the serum lipid profile, and the vascular function in healthy adults. METHODS: Thirty-eight men and 37 women with a mean ± SD age of 38.5 ± 9 y and body mass index of 24.1 ± 2.6 kg/m(2) were randomly assigned to 3 groups: a control group that did not consume coffee or a placebo and 2 groups that consumed 400 mL coffee/d for 8 wk containing a medium (MCCGA; 420 mg) or high (HCCGA; 780 mg) CGA content. Both were low in diterpenes (0.83 mg/d) and caffeine (193 mg/d). Plasma caffeic and ferulic acid concentrations were measured by GC, and the plasma AC was evaluated with use of the ferric-reducing antioxidant power method. The serum lipid profile, nitric oxide (NO) plasma metabolites, vascular endothelial function (flow-mediated dilation; FMD), and blood pressure (BP) were evaluated. RESULTS: After coffee consumption (1 h and 8 wk), caffeic and ferulic acid concentrations increased in the coffee-drinking groups, although the values of the 2 groups were significantly different (P < 0.001); caffeic and ferulic acid concentrations were undetectable in the control group. At 1 h after consumption, the plasma AC in the control group was significantly lower than the baseline value (-2%) and significantly increased in the MCCGA (6%) and HCCGA (5%) groups (P < 0.05). After 8 wk, no significant differences in the lipid, FMD, BP, or NO plasma metabolite values were observed between the groups. CONCLUSIONS: Both coffees, which contained CGAs and were low in diterpenes and caffeine, provided bioavailable CGAs and had a positive acute effect on the plasma AC in healthy adults and no effect on blood lipids or vascular function. The group that did not drink coffee showed no improvement in serum lipid profile, FMD, BP, or NO plasma metabolites. This trial was registered at registroclinico.sld.cu as RPCEC00000168.

Identification of candidate synovial membrane biomarkers after Achyranthes aspera treatment for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main symptom is a heightened inflammatory response in synovial tissues. To verify the anti-arthritic activities of Achyranthes aspera and its possible therapy-related factors on the pathogenesis of RA, the saponins in A. aspera root were isolated and identified to treat the collagen-induced arthritis (CIA) rats. Phytochemical analysis isolated and identified methyl caffeate, 25-S-inokosterone, 25-S-inokosterone ß-D-glucopyranosyl 3-(O-ß-D-glucopyranosyloxy)-oleanolate, and ß-D-glucopyranosyl 3-(O-ß-D-galactopyranosyl (1→2)(O-ß-D-glucopyranosyloxy)-oleanolate as main compounds in the root of A. aspera. Proteomics was performed to determine the differentially expressed proteins in either inflamed or drug-treated synovium of CIA rats. Treatment resulted in dramatically decreased paw swelling, proliferation of inflammatory cells, and bone degradation. Fibrinogen, procollagen, protein disulfide-isomerase A3, and apolipoprotein A-I were all increased in inflamed synovial tissues and were found to decrease when administered drug therapy. Furthermore, Alpha-1-antiproteinase and manganese superoxide dismutase were both increased in drug-treated synovial tissues. The inhibition of RA progression shows that A. aspera is a promising candidate for future treatment of human arthritis. Importantly, the total saponins found within A. aspera are the active component. Finally, autoantigens such as fibrinogen and collagen could act as inducers of RA due to their aggravation of inflammation. Given this, it is possible that the vimentin and PDIA3 could be the candidate biomarkers specific to Achyranthes saponin therapy for rheumatoid arthritis in synovial membrane.