Protective effect of bromelain on some metabolic enzyme activities in tyloxapol-induced hyperlipidemic rats.

Elevation of one or more plasma lipids, such as phospholipids, cholesterol esters, cholesterol, and triglycerides, is known as hyperlipidemia. In humans and experimental animals, bromelain, the primary active ingredient isolated from pineapple stems, has several positive effects, including anti-tumor growth, anticoagulation, and anti-inflammation. Hence, the purpose of this study was to determine the possible protective impact of bromelain on some metabolic enzymes (paraoxonase-1, glutathione S-transferase, glutathione reductase, sorbitol dehydrogenase [SDH], aldose reductase [AR], butyrylcholinesterase [BChE], and acetylcholinesterase [AChE]), activity in the heart, kidney, and liver of rats with tyloxapol-induced hyperlipidemia. Rats were divided into three groups: control group, HL-control group (tyloxapol 400 mg/kg, i.p. administered group), and HL+bromelain (group receiving bromelain 250 mg/kg/o.d. prior to administration of tyloxapol 400 mg/kg, i.p.). BChE, SDH, and AR enzyme activities were significantly increased in all tissues in HL-control compared to the control, whereas the activity of other studied enzymes was significantly decreased. Bromelain had a regulatory effect on all tissues and enzyme activities. In conclusion, these results prove that bromelain is a new mediator that decreases hyperlipidemia.

Gypensapogenin A-Liposomes Efficiently Ameliorates Hepatocellular Lipid Accumulation via Activation of FXR Receptor.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases encountered in clinical practice, which is characterized by the excessive accumulation of triglycerides (steatosis), and a variety of metabolic abnormalities including lipid metabolism and bile acid metabolism are closely related to NAFLD. In China, Gynostemma pentaphyllum is used as functional food and Chinese medicine to treat various diseases, especially NAFLD, for a long time. However, the active components that exert the main therapeutic effects and their mechanisms remain unclear. In this study, Gypensapogenin A was isolated from the total saponins of G. pentaphyllum and prepared as a liposomal delivery system. Gypensapogenin A liposomes could activate FXR, inhibit the expression of CYP7A1 and CYP8B1, increase the expression of CYP27A1, modulate the ratio of CA and CDCA, decrease the content of CA, and increase the content of CDCA, thus forming a virtuous cycle of activating FXR to play a role in lowering blood lipid levels.

Hyperlipidemia impairs bone regeneration of closed bone defects and tooth extraction wounds in mice.

OBJECTIVES: To evaluate the effect of hyperlipidemia on the healing of bone defects. MATERIALS AND METHODS: Apolipoprotein E (ApoE)-deficient mice and wild-type (WT) C57BL/6J mice were fed with an atherogenic high-fat diet (HFD) or a standard chow diet (as control) for 6 weeks. Blood samples were collected to evaluate serum lipid levels. Closed bone defects and open tooth extraction wounds were then created in the mandibles of these animals. One or two weeks after surgery, animals were euthanized. Micro-CT analysis and histomorphometric analysis were conducted to evaluate the healing of bone defects and the alveolar ridge resorption. RESULTS: Bone regeneration of closed bone defects was considerably delayed in the hyperlipidemic Apoe-/- mice and WT mice. No obvious difference was detected in the new bone formation of the tooth extraction wounds. The HFD-fed mice showed more prominent reduction in the lingual alveolar ridge height of the tooth extraction wounds when compared with the control group. CONCLUSIONS: Hyperlipidemia results in delayed bone regeneration in large closed bone defects. Although tooth extraction wounds are small and normally regenerated in a hyperlipidemic microenvironment, the prominent reduction in the alveolar ridge height is also a challenge for future restoration of the dentition.

Programmable Genome-Editing Technologies as Single-Course Therapeutics for Atherosclerotic Cardiovascular Disease.

PURPOSE OF REVIEW: To establish genome editing as a promising therapeutic approach for the treatment and prevention of atherosclerotic cardiovascular disease. RECENT FINDINGS: Systemic delivery of a CRISPR adenine base editor using lipid nanoparticles demonstrated a near 90% reduction in circulating PCSK9 and over 60% reduction in blood LDL-C in nonhuman primates with the effects remaining durable at least 8 months following a single course. Preclinical proof-of-concept studies have elucidated the superior therapeutic potential of genome-editing approaches for the treatment of hyperlipidemia, thus substantiating their progression to clinical studies.

Efficiency Assessment of Bacterial Cellulose on Lowering Lipid Levels In Vitro and Improving Lipid Metabolism In Vivo.

Bacterial cellulose (BC) is well known as a high-performance dietary fiber. This study investigates the adsorption capacity of BC for cholesterol, sodium cholate, unsaturated oil, and heavy metal ions in vitro. Further, a hyperlipidemia mouse model was constructed to investigate the effects of BC on lipid metabolism, antioxidant levels, and intestinal microflora. The results showed that the maximum adsorption capacities of BC for cholesterol, sodium cholate, Pb2+ and Cr6+ were 11.910, 16.149, 238.337, 1.525 and 1.809 mg/g, respectively. Additionally, BC reduced the blood lipid levels, regulated the peroxide levels, and ameliorated the liver injury in hyperlipidemia mice. Analysis of the intestinal flora revealed that BC improved the bacterial community of intestinal microflora in hyperlipidemia mice. It was found that the abundance of Bacteroidetes was increased, while the abundance of Firmicutes and Proteobacteria was decreased at the phylum level. In addition, increased abundance of Lactobacillus and decreased abundance of Lachnospiraceae and Prevotellaceae were obtained at the genus level. These changes were supposed to be beneficial to the activities of intestinal microflora. To conclude, the findings prove the role of BC in improving lipid metabolism in hyperlipidemia mice and provide a theoretical basis for the utilization of BC in functional food.

Purine Metabolism in Platelets and Heart Cells of Hyperlipidemic Rats.

PURPOSE: Hyperlipidemia, characterized by an increase in circulating lipid levels, doubles the chance of developing cardiovascular diseases. It prompts inflammation, immune activation, and oxidative stress in the bloodstream and organs of rats. Thus, we theorized that the metabolism of purines, an immunomodulatory mechanism, is altered in cells involved in the development of cardiovascular diseases. METHODS: Therefore, we induced acute hyperlipidemia in Wistar rats with Poloxamer-407 and euthanized the animals 36 h later. The leucocyte differential, the rate of purine metabolism on the surface of platelets and heart cells, and markers of oxidative stress in the heart tissue were evaluated. These parameters were also assessed in animals pretreated for 30 days with curcumin and/or rutin. RESULTS: Hyperlipidemia increased the hydrolyses of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) in platelets. In heart cells, the metabolism of ATP and adenosine (ADO) were increased, while ADP hydrolysis was reduced. Additionally, lipid damage and antioxidant defenses were increased in heart homogenates. Hyperlipidemic rats also exhibited a reduced percentage of eosinophils and lymphocytes. CONCLUSION: Together, these findings are indicative of an increased risk of developing cardiovascular diseases in hyperlipidemic rats. The pretreatments with antioxidants reverted some of the changes prompted by hyperlipidemia preventing detrimental changes in the cells and tissues. Graphical Abstract.

Enhancing the Hypolipidemic Effect of Simvastatin in Poloxamer-Induced Hyperlipidemic Rats via Liquisolid Approach: Pharmacokinetic and Pharmacodynamic Evaluation.

This study aimed to enhance the dissolution of simvastatin (SMV) through its formulation in liquisolid tablets (LSTs) to improve its bioavailability and hypolipidemic activity after oral administration. SMV-LSTs were optimized using Box-Behnken design to maximize the rate and extent of SMV dissolution. The optimized SMV-LST was evaluated for pharmacokinetic parameters and potential hypolipidemic activity on induced hyperlipidemic rats. The dissolution parameters revealed a shortening of mean dissolution time from 10.99 to 6.82 min, increasing of dissolution rate during the first 10 min from 1253.15 to 1667.31 µg/min, and enhancing of dissolution efficiency after 60 min from 71.92 to 86.93% for SMV-LSTs versus the commercial SMV tablets. The obtained data reflected an improvement in the relative bioavailability of SMV with 148.232% which was confirmed by the significant reduction of the levels of circulating total cholesterol, triglycerides that reached the normal level after 12 h. In particular, the optimized SMV-LSTs reduced serum low-density lipoproteins (LDL) by 44.6% which was significantly different from the commercial SMV tablets. In contrast, the level of serum high-density lipoprotein (HDL) was significantly augmented after 4 h in rats treated with the optimized SMV-LSTs by 47.6%. Finally, the optimized SMV-LSTs showed a significant lower atherosclerotic index value which could maximize its potential in decreasing the risk of coronary disease and atherosclerosis. Overall enhancement in pharmacokinetics and pharmacodynamics in comparison with the commercial tablets confers the potential of the liquisolid approach as a promising alternative for improved oral bioavailability, hypolipidemic, and cardioprotective effects of SMV. Graphical abstract.

[Gegen Qinlian Decoction formula syndrome and its application in diabetes, hypertension, hyperlipidemia and obesity].

Gegen Qinlian Decoction can be used to treat intestinal dampness and heat. In addition to diarrhea diseases, it is also commonly used in the treatment of diabetes, hypertension, hyperlipidemia, obesity and other chronic metabolic diseases. It can not only alleviate symptoms, but also reduce blood sugar, blood pressure, lipid and weight. Neck stiffness, blush, red lips, red tongue, dry mouth, sweating, palpitation, insomnia and feces are the key indications of Gegen Qinlian Decoction. It can be used alone to reduce blood sugar for diabetes mellitus. In the treatment of hypertension, it can reduce blood pressure when being used alone or combined with Tianma Gouteng Yin or Chaihu Jia Longgu Muli Decoction. Large dose(30-120 g) of Pueraria lobata is the key to the effect of Gegen Qinlian Decoction.

Modulation of Lipid Metabolism by Celastrol.

Hyperlipidemia, characterized by high serum lipids, is a risk factor for cardiovascular disease. Recent studies have identified an important role for celastrol, a proteasome inhibitor isolated from Tripterygium wilfordii Hook. F., in obesity-related metabolic disorders. However, the exact influences of celastrol on lipid metabolism remain largely unknown. Celastrol inhibited the terminal differentiation of 3T3-L1 adipocytes and decreased the levels of triglycerides in wild-type mice. Lipidomics analysis revealed that celastrol increased the metabolism of lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), sphingomyelins (SMs), and phosphatidylethanolamines (PEs). Further, celastrol reversed the tyloxapol-induced hyperlipidemia induced associated with increased plasma LPCs, PCs, SMs, and ceramides (CMs). Among these lipids, LPC(16:0), LPC(18:1), PC(22:2/15:0), and SM(d18:1/22:0) were also decreased by celastrol in cultured 3T3-L1 adipocytes, mice, and tyloxapol-treated mice. The mRNAs encoded by hepatic genes associated with lipid synthesis and catabolism, including Lpcat1, Pld1, Smpd3, and Sptc2, were altered in tyloxapol-induced hyperlipidemia, and significantly recovered by celastrol treatment. The effect of celastrol on lipid metabolism was significantly reduced in Fxr-null mice, resulting in decreased Cers6 and Acer2 mRNAs compared to wild-type mice. These results establish that FXR was responsible in part for the effects of celastrol in controlling lipid metabolism and contributing to the recovery of aberrant lipid metabolism in obesity-related metabolic disorders.

Rutin and curcumin reduce inflammation, triglyceride levels and ADA activity in serum and immune cells in a model of hyperlipidemia.

Hyperlipidemia is associated with endothelial dysfunction and inflammatory disorders. Adenosine and adenosine deaminase (ADA) modulate immune responses and lipid metabolism. Curcumin and rutin are polyphenols with antioxidant, anti-inflammatory, and hypolipidemic effects. We evaluated the action of rutin and curcumin in the lipid levels and inflammation, as well as their effect on ADA activity in serum, lymphocytes, platelets, and neutrophils of hyperlipidemic rats. Adult male Wistar rats pretreated with curcumin and/or rutin for 30 days were submitted to Poloxamer-407- induced hyperlipidemia. Biochemical, hematological, and oxidative stress parameters, as well as serum and extracellular ADA activity, were performed 36h post-induction. Hyperlipidemia was confirmed by the increase in total cholesterol (TC) and triglycerides (TG). Hematological alterations, elevated reactive oxygen species (ROS) levels, and increased myeloperoxidase (MPO) and ADA activities were observed in hyperlipidemic rats. Curcumin and the curcumin/rutin association decreased TG and increased high-density lipids (HDL) levels. The pretreatments prevented changes in the hematological parameters, decreased the activities of MPO in plasma and ADA in serum and cells. Cholesterol and ROS levels were not altered by the pretreatments. Our results show that pretreatments with rutin and/or curcumin prevent the hyperlipidemia-induced inflammation. Pretreatments with curcumin and/or rutin are potential complementary therapies in the prevention of hypertriglyceridemia and inflammation.

Association of CYP1A1 rs1048943 variant with aggressive periodontitis and its interaction with hyperlipidemia on the periodontal status.

BACKGROUND AND OBJECTIVE: CYP1A1 rs1048943 polymorphism was reported to be correlated with periodontitis; however, its association with aggressive periodontitis (AgP) has not yet been investigated. The aim of the study was to investigate the association between the CYP1A1 gene rs1048943 variant with generalized aggressive periodontitis (GAgP) and platelet activation and analyse whether its interaction with hyperlipidemia affects periodontal status in a Chinese population. METHODS: A case-control study of 224 GAgP patients and 139 healthy controls was conducted. The clinical parameters of probing depth (PD), attachment loss (AL) and bleeding index (BI) were recorded. Platelet count (PLT), platelet distribution width (PDW), platelet large cell ratio (PLCR), mean platelet volume (MPV), serum total cholesterol (TC), triacylglycerol (TG), high and low-density lipoprotein (HDL and LDL) were also measured. The CYP1A1 rs1048943 SNP was genotyped by time-of-flight mass spectrometry. Logistic and linear regression models were used to measure correlation. RESULTS: The CYP1A1 rs1048943 AG/GG genotype was associated with GAgP (OR = 1.56, 95%CI: 1.01, 2.42), PD, AL and decreased PDW, PLCR and MPV after adjustment for covariates. Gene-lipid interactions were found between CYP1A1 rs1048943 and HDL for PD (Pinteraction  = 0.0033), BI (Pinteraction  = 0.0311) and AL (Pinteraction  = 0.0141) and between CYP1A1 rs1048943 and LDL for PD (Pinteraction  = 0.013) among patients with GAgP. CONCLUSION: The G allele of the CYP1A1 rs1048943 gene was associated with GAgP, periodontal status and platelet-related inflammation status in a Chinese population. Hyperlipidemia could modulate the effect of CYP1A1 rs1048943 on the periodontal status of GAgP.

Inhibition Effect of Triglyceride Accumulation by Large Yellow Croaker Roe DHA-PC in HepG2 Cells.

The phospholipids (PLs) of large yellow croaker (Pseudosciaena crocea, P. crocea) roe contain a high level of polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), which can lower blood lipid levels. In previous research, PLs of P. crocea roe were found able to regulate the accumulation of triglycerides. However, none of these involve the function of DHA-containing phosphatidylcholine (DHA-PC), which is the main component of PLs derived from P. crocea roe. The function by which DHA-PC from P. crocea roe exerts its effects has not yet been clarified. Herein, we used purified DHA-PC and oleic acid (OA) induced HepG2 cells to establish a high-fat model, and the cell activity and intracellular lipid levels were then measured. The mRNA and protein expression of Fatty Acid Synthase (FAS), Carnitine Palmitoyl Transferase 1A (CPT1A) and Peroxisome Proliferator-Activated Receptor α (PPARα) in HepG2 cells were detected via RT-qPCR and western blot as well. It was found that DHA-PC can significantly regulate triglyceride accumulation in HepG2 cells, the effect of which was related to the activation of PPARα receptor activity, upregulation of CPT1A, and downregulation of FAS expression. These results can improve the understanding of the biofunction of hyperlipidemia mediated by DHA-PC from P. crocea roe, as well as provide a theoretical basis for the utilization of DHA-PC from P. crocea roe as a functional food additive.

Synthesis of Novel Benzimidazole-2-carboxamide Derivatives and in Vivo Antihyperlipidemic Activity Evaluation.

Hyperlipidemia is known as an elevation of plasma lipid components. It contributes significantly to atherosclerosis which is one of the most important causative factors in cardiovascular diseases. Agents that cause a dramatic decrease in serum lipid levels are of great value in the treatment of cardiovascular diseases. For this purpose, a new series of benzimidazole propyl carboxamide benzophenone derivatives have been synthesized (7, 8, and 9). These compounds were tested in vivo to evaluate their potential hypolipidemic activity using Triton WR-1339 induced hyperlipidemic rats. All the synthesized compounds have proved to be highly biologically active, with compound 9 being the most active derivative.

The effect of menopause on the relationship between hyperlipidemia and periodontal disease via salivary 8-hydroxy-2'-deoxyguanosine and myeloperoxidase levels.

OBJECTIVE: Impairment of the lipid metabolism could affect the periodontal disease; increased oxidative stress may have a role in this relationship. The aim of the present study was to evaluate the role of menopause in the relationship between hyperlipidemia and periodontal disease via oxidative stress markers in saliva. MATERIALS AND METHODS: Sixty-seven women were enrolled in the study and divided into four groups as systemically healthy and premenopause (C) (n = 18), hyperlipidemia and premenopause (H) (n = 16), systemically healthy and postmenopause (M) (n = 17), and hyperlipidemia and postmenopause (MH) (n = 16). Sociodemographics, periodontal and metabolic parameters, and saliva oxidative markers (myeloperoxidase [MPO] and 8-hydroxy-2'-deoxyguanosine [8-OHdG]) were evaluated. RESULTS: Menopause and/or hyperlipidemia were associated with an increase in all evaluated periodontal parameters. Saliva 8-OHdG and MPO levels were higher in menopausal groups (M and MH). Multivariate linear regression analyses revealed that hyperlipidemia was related to an increase in periodontal parameters. Salivary oxidative stress markers and periodontal parameters were also positively associated with menopause and hyperlipidemia. CONCLUSION: Saliva 8-OHdG and MPO levels may indicate that the relationship between periodontal disease and hyperlipidemia is aggravated by menopause.

N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide decreases triglyceride levels by downregulation of Apoc3 gene expression in acute hyperlipidemic rat model.

Hyperlipidemia is a known cause of coronary vascular diseases, which is a major cause of death in many parts of the world. Targeting several pathways that lead to increase in lipid profiles is of great potential to control diseases. 1H-indole-2-carboxamide derivatives were tested for their hypolipidemic activity at the molecular level in comparison with bezafibrate. The gene expression profiles of lipoprotein signaling and cholesterol metabolism and fatty acid metabolism PCR arrays were determined in rats with acute hyperlipidemia induced by Triton WR1339. Lipid profiles of serum from treated rats showed significant hypolipidemic effect by the compounds. Several genes of potential interest were reported to be overexpressed by Triton WR1339 including Apoc3, Apob, Hmgcs2, Apoa1, Apoe, Apof, acsl1, and Decr1. Most of the overexpressed genes were downregulated by N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide with significant decreases in Apoc3, Apob, Acaa2, Acsl1, and Slc247a5 gene expression levels. N-(4-Benzoylphenyl)-1H-Indole-2-Carboxamide and bezafibrate did not significantly affect the gene expression levels which were increased with acute hyperlipidemia induced by Triton WR1339. In conclusion, gene expression profiling identified the possible mechanism in which Triton WR1339 induces its acute hyperlipidemic effect which was reversed by the use of N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide.

Evaluation of DNA damage in Wistar rat tissues with hyperlipidemia induced by tyloxapol.

Hyperlipidemia is characterized by high levels of plasma triglycerides and LDL-cholesterol, accompanied by reduced HDL-cholesterol levels, and is often associated with an increased risk of cardiovascular diseases. However, few studies have shown the effects of hyperlipidemia on genomic stability. The aim of this study was to evaluate DNA damage provided by tyloxapol induced hyperlipidemia. Tyloxapol, a non-ionic surfactant, which increases the activity of the enzyme HMG-CoA reductase and decreases clearance of lipoproteins, was used to induce hyperlipidemia in Wistar rats. Genomic instability was assessed using the comet assay which evaluates DNA strand breaks in several tissues, and the micronucleus assay in bone marrow to detect chromosomal mutagenicity for clastogenic and/or aneugenic effects. Biochemical analyses confirmed hyperlipidemia in tyloxapol-treated rats, accompanied by hyperglycemia. Higher creatinine and urea levels were observed, suggesting kidney injury. The comet assay indicated increased DNA damage in blood, liver, and kidney, but not in brain tissue. However, no increase in micronucleus frequency was observed, indicating lack of mutagenic effects. Simvastatin, used as lipid lowering drug, decreased cholesterol and triglycerides in rats treated with tyloxapol. Those findings indicate that tyloxapol-induced hyperlipidemia is able to increase genomic instability, which is associated with higher cancer risk. Therefore, this surfactant might be used in models to evaluate new hypolipidemic drugs with associated chemopreventive properties.

Cuboidal lipid polymer nanoparticles of rosuvastatin for oral delivery.

The present work aimed to develop and characterize sustained release cuboidal lipid polymeric nanoparticles (LPN) of rosuvastatin calcium (ROS) by solvent emulsification-evaporation process. A three factor, two level (23) full-factorial design was applied to study the effect of independent variables, i.e. amount of lipid, surfactant and polymer on dependent variables, i.e. percent entrapment efficiency and particle size. Optimized formulations were further studied for zeta potential, TEM, in vitro drug release and ex vivo intestinal permeability. Cuboidal nanoparticles exhibited average particle size 61.37 ± 3.95 nm, entrapment efficiency 86.77 ± 1.27% and zeta potential -6.72 ± 3.25 mV. Nanoparticles were lyophilized to improve physical stability and obtain free-flowing powder. Effect of type and concentration of cryoprotectant required to lyophilize nanoparticles was optimized using freeze-thaw cycles. Mannitol as cryoprotectant in concentration of 5-8% w/v was found to be optimal providing zeta potential -20.4 ± 4.63 mV. Lyophilized nanoparticles were characterized using FTIR, DSC, XRD and SEM. Absence of C=C and C-F aromatic stretch at 1548 and 1197 cm-1, respectively, in LPN indicated coating of drug by lipid and polymer. In vitro diffusion of ROS using dialysis bag showed pH-independent sustained release of ROS from LPN in comparison to drug suspension. Intestinal permeability by non-everted gut sac model showed prolonged release of ROS from LPN owing to adhesion of polymer to mucus layer. In vivo absorption of ROS from LPN resulted in 3.95-fold increase in AUC0-last and 7.87-fold increase in mean residence time compared to drug suspension. Furthermore modified tyloxapol-induced rat model demonstrated the potential of ROS-loaded LPN in reducing elevated lipid profile.

Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile.

Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

Fucoidan improves serum lipid levels and atherosclerosis through hepatic SREBP-2-mediated regulation.

Hyperlipidemia is associated with increased risk of the development of cardiovascular diseases. Although a great deal of attention has been paid to the hypolipidemic activity of fucoidan, complex polysaccharides from brown seaweeds, the underlying mechanism is still unclear. This study was performed to investigate whether and how fucoidan has lipid-lowering potential in poloxamer-407 (P407)-induced hyperlipidemic mice. Fucoidan treatment 2 h after acute administration of P407 in these mice significantly reduced serum total cholesterol, triglycerides, and LDL cholesterol levels, but increased the levels of HDL cholesterol. In HepG2 hepatocytes and the liver, fucoidan decreased the expression of FAS and ACC mRNA with no or only a moderate inhibitory effect on SREBP-1c mRNA expression. Furthermore, fucoidan attenuated the hepatic expression of mature SREBP-2 protein with a subsequent decrease in hepatic HMG-CoA reductase mRNA expression and an increase in hepatic LDL receptor mRNA expression. In addition, atherosclerotic lesions in the aorta of chronically P407-treated mice were also reduced by fucoidan. These findings indicate that fucoidan improves serum lipid levels by regulating the expression of key enzymes of cholesterol and triglyceride syntheses in the liver through modulation of SREBP-2.

The effect of increased lipoproteins levels on the disposition of vincristine in rat.

BACKGROUND: Vincristine (VCR), an antineoplastic agent, is a key component in the treatment of acute lymphoblastic leukemia, lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor diseases. Recently, high incidence of hyperlipidemia was reported to be associated with allogenic hematopoietic stem cell transplantation and VCR/L-asparaginase therapy. The aim of this study is to test the effects of incremental increase in lipoproteins levels on vincristine disposition in rat. METHOD: To study VCR pharmacokinetics and protein binding, rats (n = 25) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by ip injection of (1 g/Kg) poloxamer 407 in rats. Serial blood samples were collected using the pre-inserted jugular vein cannula for 72 h post VCR (0.15 mg/Kg) i.v. dose. VCR unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits. RESULTS: VCR demonstrated a rapid distribution phase (6-8 h) followed by a slower elimination phase with a mean elimination t½ of ~ 14 h. VCR exhibited moderate binding to plasma proteins ~ 83 %. It showed a relatively small Vc (~0.17 L/Kg) and a larger Vß (1.53 L/Kg) indicating good tissue distribution. As the lipoproteins levels were increased, no significant changes were noted in VCR unbound fraction, plasma concentration, or volume of distribution indicating low affinity to lipoprotein binding. Induced HL also did not affect VCR elimination where similar VCR AUC0-∞, Cl and elimination phase t½ were reported along the different lipemic groups. CONCLUSION: Incremental increase in lipoprotein levels resulted in no significant effect on VCR disposition as such ALL malignant lymphoma and allogenic hematopoietic stem cell transplantation patients need not to worry about HL-VCR interaction. Whether, HL can potentiate another drug-drug or drug-disease interaction involving VCR warrants further studying and monitoring to ensure therapeutic safety and efficiency.