HDL and cancer - causality still needs to be confirmed? Update 2020.

An inverse correlation between high-density lipoprotein cholesterol (HDL-C) and cancer risk has been shown by several epidemiological studies. Some studies have even suggested that HDL-C can be used as a prognostic marker in patients with certain types of cancer. However, whether reduced HDL-C level is a consequential or causal factor in the development and progression of cancer remains a controversial issue. In this review, we update and summarize recent advances that highlight the role of HDL and some of its components in prognosis, diagnosis and treatment of cancer.

Antioxidant Effects of Trehalose in an Experimental Model of Type 2 Diabetes.

BACKGROUND: Oxidative stress that occurs as a consequence of the imbalance between antioxidant activity and free radicals can contribute in the pathogenesis of metabolic disorders, such as type 2 diabetes mellitus (T2DM). Antioxidant therapies have been proposed as possible approaches to treat and attenuate diabetic complications. The purpose of this study was to evaluate potential antioxidant effects of trehalose on oxidative indices in a streptozotocin (STZ)-induced diabetic rat model. METHODS: Diabetic rats were divided randomly into five treatment groups (six rats per group). One test group received 45 mg/kg/day trehalose via intraperitoneal injection, and another received 1.5 mg/kg/day trehalose via oral gavage for 4 weeks. Three control groups were also tested including nondiabetic rats as a normal control (NC), a nontreated diabetic control (DC), and a positive control given 200 mg/kg/day metformin. Levels of thiol groups (-SH), and serum total antioxidant capacity were measured between control and test groups. In addition, superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities were assessed. RESULTS: In both oral and injection trehalose-treated groups, a marked increase was observed in serum total antioxidant capacity (TAC) (p > 0.05) and thiol groups (-SH) (p < 0.05). Also, SOD and GPx activities were increased after 4 weeks of treatment with trehalose. CONCLUSION: In conclusion, the present results indicate ameliorative effects of trehalose on oxidative stress, with increase antioxidant enzyme activities in STZ-induced diabetic rats.

Protective Effects of Intravenous Magnesium Sulfate in Stroke Patients Receiving Amiodarone: A Randomized Controlled Trial.

Anti-arrhythmic agents, like amiodarone, interfere at different stages of the ischemic stroke. However, amiodarone was accompanied with immunological pulmonary complications and adverse neurological effects. We hypothesize that magnesium sulfate in combination with amiodarone holds promise for stroke treatment. Thirty-six patients with confirmed diagnosis of ischemic stroke and atrial fibrillation who received bolus amiodarone were randomly assigned to magnesium sulfate every 24 h or similar volume of normal saline (as placebo) for 5 days. Various severity test scores were used to evaluate the symptoms. Routing biochemistry were also measured at days 1 and 5. Treatment with MgSO4 results in a significant reduction in serum levels of NGAL, Hb, T.Bill, IL-6, IL-8, SNSE, S100B, EGF, PAF, CRP and IgG. Also, MgSO4 treatment significantly improved the RASS, Candida, SOFA, NIHSS and APACHE scores. Moreover, reduction of IL-6, IL-8, SNSE, EGF and APACHE score and increase in RASS score were significantly higher in MgSO4 group compared with placebo. Intravenous administration of MgSO4 in amiodarone-treated stroke patients improved the inflammatory, immunological and neurological indicators and reduced disability in ICU-admitted AIS patients, suggesting that this treatment scheme may prevent amiodarone-induced complications in these patients.

Curcumin nanofibers for the purpose of wound healing.

Poor wound healing is a highly prevalent clinical problem with, as yet, no entirely satisfactory solution. A new technique, termed electrospinning, may provide a solution to improve wound healing. Due to their large surface area to volume ratio and porosity, the nanofibers created by electrospinning are able to deliver sustained drug release and oxygen to the wound. Using different types of polymers with varying properties helps strengthening nanofiber and exudates absorption. The nanofibers appear to have an ideal structure applicable for wound healing and, in combination with curcumin, can blend the anti-inflammatory and antioxidant properties of curcumin into a highly effective wound dressing. The use of suitable curcumin solvents and the slow release of curcumin from the nanofiber help in overcoming the known limitations of curcumin, specifically its low stability and limited bioavailability. Here, we review the studies which have been done on synthesized nanofibers containing curcumin, produced by the electrospinning technique, for the purpose of wound healing.

Curcuminoids plus piperine improve nonalcoholic fatty liver disease: A clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) as a prevalent hepatic disease is associated with an increased risk of morbidity and mortality related to the liver and cardiovascular disease (CVD). Lifestyle modification and good metabolic control is the first line of treatment, but not always efficacious in reversing NAFLD pathogenesis. Curcumin is a dietary phytochemical with hepatoprotective activities, though its low bioavailability is considered as a major challenge for clinical applications. Therefore, in this study, in order to improve the bioavailability of curcumin, it was coadministered with piperine and we investigated the effects of this bioavailability-enhanced curcumin on serum hepatic enzymes, lipid profile, and glycemic indices in patients with NAFLD. METHODS: In this randomized controlled parallel-group trial, 70 subjects with ultrasound-determined NAFLD were randomized to either 500 mg curcuminoids coadministered with 5 mg piperine daily or placebo for 12 weeks. NAFLD severity (on the basis of sonography) and hepatic function was assessed at baseline and at the study end. RESULTS: Seventy subjects completed the study. Supplementation with curcuminoids plus piperine significantly reduced the hematocrit (P = 0.027), erythrocyte sedimentation rate (P = 0.048) and the serum concentrations of alanine aminotransferase (P = 0.035), aspartate aminotransferase (P = 0.042), alkaline phosphatase (P = 0.004), cholesterol (P < 0.016), low-density lipoprotein cholesterol (P < 0.017), Iron (P = 0.026), and Hemoglobin (P = 0.025) and increased total iron-binding capacity (P = 0.003). However, except albumin, changes in other parameters were not statistically different between groups. In addition, administration of curcuminoids plus piperine significantly improved NAFLD severity (P < 0.001), which was statistically different compared with the placebo group (P = 0.022). Also, the percentage of improved patients was marginally higher in the curcuminoids plus piperine group when compared with the placebo group (P = 0.058). CONCLUSION: This study suggested beneficial effects of combined curcuminoids and piperine supplementation on disease severity in patients with NAFLD.

The role of high-density lipoproteins in antitumor drug delivery.

High-density lipoproteins (HDLs) are the smallest lipoprotein with the highest level of protein in their surface. The main role of HDLs are reverse transport of cholesterol from peripheral tissues to the liver. More recently, HDLs have been considered as a new drug delivery system because of their small size, proper surface properties, long circulation time, biocompatibility, biodegradability, and low immune stimulation. Delivery of anticancer drug to the tumor tissue is a major obstacle against successful chemotherapy, which is because of the toxicity and poor aqueous solubility of these drugs. Loading chemotherapeutic drugs in the lipid core of HDLs can overcome the aforementioned problems and increase the efficiency of drug delivery. In this review, we discuss the use of HDLs particles in drug delivery to the tumor tissue and explain some barriers and limitations that exist in the use of HDLs as an ideal delivery vehicle.

Monocyte-to-HDL-cholesterol ratio as a prognostic marker in cardiovascular diseases.

Inflammation and lipid accumulation are two basic hallmarks of atherosclerosis as a chronic disease. Inflammation not only is a local response but can also be considered as a systemic process followed by an elevation of inflammatory mediators. Monocytes are a major source of proinflammatory species during atherogenesis. In atherosclerosis, modified low-density lipoproteins (LDLs) are removed by macrophages; these are recruited in the vessel wall, inducing the release of inflammatory cytokines in inflamed tissue. Hence, inflammatory cholesterol ester-loaded plaque is generated. High-density lipoprotein-cholesterol (HDL-C) exhibits antiatherosclerotic effects by neutralizing the proinflammatory and pro-oxidant effects of monocytes via inhibiting the migration of macrophages and LDL oxidation in addition to the efflux of cholesterol from these cells. Furthermore, HDL plays a role in suppressing the activation of monocytes and proliferation-differentiation of monocyte progenitor cells. Thus, accumulation of monocytes and reduction of HDL-C may participate in atherosclerosis and cardiovascular diseases (CVD). Given that the relationship between the high number of monocytes and low HDL-C levels has been reported in inflammatory disorders, this review focused on understanding whether the monocyte-to-HDL ratio could be a convenient marker to predict atherosclerosis development and progression, hallmarks of CV events, instead of the individual monocyte count or HDL-C level.

Gene therapy in cardiovascular diseases: A review of recent updates.

Gene therapy is considered as a promising approach for treating cardiac dysfunction. In this review, we evaluated the clinical trials assessing gene therapy in cardiovascular diseases (CVD) from 2000 to 2017. PubMed and ClinicalTrials.gov (only English language) were searched for clinical trials published between January 2000 and May 2017, using the search terms "gene transfer" OR "gene therapy" and "cardiovascular diseases" and related terms. The trials with sample size lower than 10 patients were excluded. Twenty-six clinical trials on human and animals, including 1543 patients were listed and evaluated. The sample size in 14 trials was lower than 100 patients and in seven trials lower than 20 patients. Eleven trials used plasmid DNA and eight trials used adenovirus, one study used plasmid DNA, adenovirus, and liposome. We detected that gene therapy was a safe approach and improved the symptoms of CVD; however, the effect of gene therapy on the cardiac dysfunction is controversial.

Effects of curcumin on HDL functionality.

Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function.

Investigation of the effects of curcumin on serum cytokines in obese individuals: a randomized controlled trial.

BACKGROUND: Obesity is a disorder often accompanied by a heightened state of systemic inflammation and immunoactivation. The present randomized crossover trial aimed to investigate the efficacy of curcumin, a bioactive polyphenol with established anti-inflammatory and immunomodulatory effects, on the serum levels of a panel of cytokines and mediators in obese individuals. METHODS: Thirty obese individuals were randomized to receive curcumin at a daily dose of 1 g or a matched placebo for 4 weeks. Following a 2-week wash-out period, each group was assigned to the alternate treatment regimen for another 4 weeks. Serum samples were collected at the start and end of each study period. Serum levels of IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFNγ, EGF, MCP-1, and TNF α were measured using a multiplex Biochip Array Technology based method. RESULTS: Mean serum IL-1ß (P = 0.042), IL-4 (P = 0.008), and VEGF (P = 0.01) were found to be significantly reduced by curcumin therapy. In contrast, no significant difference was observed in the concentrations of IL-2, IL-6, IL-8, IL-10, IFNγ, EGF, and MCP-1. CONCLUSIONS: The findings of the present trial suggested that curcumin may exert immunomodulatory effects via altering the circulating concentrations of IL-1ß, IL-4, and VEGF.

Lipidomic profiling in patients with familial hypercholesterolemia: Abnormalities in glycerolipids and oxysterols.

OBJECTIVES AND AIM: This study aimed to identify precise biomarkers and develop targeted therapeutic strategies for preventing premature atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH) by investigating the quantitative and qualitative abnormalities in the metabolic network of lipids in these patients using an advanced lipidomics platform. DESIGN & METHODS: The study population comprised 18 homozygous (HoFH), 18 heterozygous (HeFH) FH patients, and 20 healthy controls. Cholesterol oxidation products (oxysterol, COPs) and main lipid classes were determined using gas chromatography-mass spectrometry. Results were expressed as percentages of total fat matter for lipid classes and percentages of total COPs for oxysterols. The principal component analysis (PCA) was also carried out, to highlight the correlation between studied parameters and groups investigated. RESULTS: Patients (both HoFH and HeFH) showed lower content of free fatty acids (FFAs) and greater values of triacylglycerols (TAGs) in comparison to controls. HoFH showed lower monoacylglycerols (P<0.01) and higher free cholesterol (FC) (P<0.05) when compared to HeFH and controls. The total content of COPs ranged from 1.96 to 4.25 mg/dL, from 2.27 to 4.05 mg/dL, and from 0.79 to 4.12 mg/dL in healthy controls, HoFH and HeFH groups, respectively, with no significant differences between patients and controls. In general, the 7α-hydroxycholesterol (7α-HC) was greater than other COPs. However, no significant differences were found between the three studied groups. Moreover, an opposite trend was observed between 7α-HC and 7-ketocholesterol (7-KC). Additionally, when PCA was carried out, the first two PCs explained 92.13 % of the total variance, of which the PC1 describes 53.94 % of variance mainly correlated to TAGs, diacylglycerols (DAGs), and 7-KC. On the other hand, the PC2 was correlated primarily for FFAs, FC and esterified sterols (E-STE). CONCLUSIONS: In conclusion, abnormal levels of TAGs, DAGs and 7-KC were associated with HeFH while HoFH was associated with the abnormal amount of E-STE.

Gait speed, handgrip strength, and their combination, and risk of depression in later life: Evidence from a prospective study of community-dwelling older adults.

OBJECTIVE: This study investigated the association between gait speed, handgrip strength, and their combination, and the risk for developing clinically relevant depressive symptoms in community-dwelling older adults. METHODS: A secondary analysis was conducted using data from the ASPirin in Reducing Events in the Elderly study. Participants were community-dwelling older adults in Australia and the United States of America followed for a median (interquartile range) of 3.97 (2.26) years. Baseline handgrip strength and gait speed were used as exposure variables, and their combination categories were also explored. Depression was measured using the modified Center for Epidemiological Studies Depression 10-item scale (CES-D 10). Cox regression was used to estimate Adjusted Hazard Ratios (AHR) with 95 % Confidence Intervals (CI) after adjusting for a range of potential confounders. RESULT: A total of 17,231 participants (55.3 % women) were included in the analysis. Slow gait and weak grip at baseline were associated with the risk of depression (AHR: 1.20; CI: 1.11-1.29 and 1.14; 1.06-1.23, respectively). The combination of the two physical performance measures was associated with a 31 % increase in the risk of depression (1.31; 1.16-1.47) and a significant dose-response association was observed for quintiles of gait and grip with depression. LIMITATIONS: Although the CES-D 10 is a validated scale, it is a self-reported tool rather than a clinical diagnosis of depression. CONCLUSION: Low physical function may be a risk factor for depression in older adults. This highlights the inextricable link between the physical and mental health of older adults, which can inform potential clinical and public health prevention strategies for depression in later life.

Capacity of HDL to Efflux Cellular Cholesterol from Lipid-Loaded Macrophages Is Reduced in Patients with Familial Hypercholesterolemia.

This study aimed to evaluate the high-density lipoprotein (HDL) capacity to efflux cellular cholesterol from lipid-loaded macrophages to find a reliable and low-cost biomarker with the purpose of better evaluating the risk of premature cardiovascular (CV) events in FH patients. This case-controlled study comprised 16 homozygous (HOFH) and 18 heterozygous (HEFH) FH patients, as well as 20 healthy subjects recruited as controls. Two main subfractions of HDL (HDL2 (d = 1.063-1.125 g/mL) and HDL3 (d = 1.125-1.210 g/mL)) were isolated from the patients' serum samples using sequential ultracentrifugation. After compositional characterization, the capacity of HDL to efflux cholesterol (CEC%) from lipid-laden macrophages was measured. The HDL2 and HDL3 subfractions showed some differences in lipid and protein composition between the studied groups. In addition, both HDL subfractions (p < 0.001) revealed significantly reduced CEC% in HOFH patients (HDL2: 2.5 ± 0.1 and HDL3: 3.2 ± 0.2) in comparison with the HEFH (HDL2: 3.2 ± 0.1% and HDL3: 4.1 ± 0.2%) and healthy (HDL2: 3.3 ± 0.2% and HDL3: 4.5 ± 0.3%) subjects. Additionally, multinomial logistic regression results indicated that the CEC% of both HDL2 (OR: 0.091; 95% CI: 0.018-0.452, p < 0.01) and HDL3 (OR: 0.118; 95% CI: 0.035-0.399, p < 0.01) subfractions are strongly and inversely associated with the homozygous form of FH. A decreased capacity of HDL particles to efflux cholesterol from macrophages might identify homozygous FH patients who are at elevated risk for premature CVDs. Prospective studies with a large sample size are warranted to evaluate this hypothesis.

The effect of PCSK9 immunization on the hepatic level of microRNAs associated with the PCSK9/LDLR pathway.

Introduction: MicroRNAs (miRNAs) are a class of gene expression epigenetic regulators that play roles in regulating genes involved in cholesterol homeostasis, including low-density lipoprotein receptor (LDLR) and PCSK9; therefore, miRNAs have been suggested as potential therapeutic targets for treating cardiometabolic disorders. Thus, the present study aimed to assess the effect of immunotherapy with the PCSK9 peptide vaccine on the hepatic expression levels of microRNAs associated with the LDLR pathway, including miRNA-27a, miRNA-30c, and miRNA-191, in normal vaccinated mice. Material and methods: PCSK9 immunogenic peptide and 0.4% alum adjuvant were mixed at a 1 : 1 ratio and used as a vaccine formulation. Male albino mice were randomly assigned to the vaccine or control group. Mice in the vaccine group were injected four times at two-week intervals with a PCSK9 peptide vaccine, and mice in the control group were injected with phosphate-buffered saline (PBS). Animal livers were sampled 2 weeks after the last injection to assess miRNA expression levels. The hepatic expression levels of miRNA-27a, miRNA-30c, and miRNA-191 were evaluated by SYBR Green real-time PCR, quantified by a comparative (2- Δ Δ CT) method (fold change (FC)) and normalized to U6 small nuclear RNA (U6snRNA) expression as an internal control. Results: The hepatic expression level of miRNA-27a was significantly lower in mice following immunotherapy with the PCSK9 peptide vaccine compared to the control group (FC: 0.731 ±0.1, p = 0.027). Also, there was a borderline significantly lower hepatic expression level of miRNA-30c in the vaccinated group compared to the control (FC: 0.569 ±0.1, p = 0.078). However, no significant differences were found in the hepatic expression level of miRNA-191 between the two studied groups (FC: 0.852 ±0.1, p = 0.343). Conclusions: According to the findings, the PCSK9 peptide vaccine could effectively reduce the hepatic expression level of miRNA-27a and may be helpful in the management of LDL-C level and atherosclerosis, which may be mediated through the LDLR pathway.

The Immunogenic Potential of PCSK9 Peptide Vaccine in Mice.

AIM: To evaluate the immunogenic potential of the carrier-free peptide-based anti-PCSK9 (proprotein convertase subtilisin/kexin 9) vaccine in albino mice. METHODS: The immunogenic pcsk9 peptide and 0.4% alum adjuvant were mixed thoroughly at a 1:1 ratio and used as a vaccine formulation. To assess the humoral immune response, animals' blood was sampled two weeks after the last immunization. The ELISA method was employed to measure serum anti-PCSK9 antibody titers, PCSK9 concentrations, and PCSK9/LDLR interaction. RESULTS: ELISA analysis showed significant induction of IgG antibody titers by PCSK9 peptide vaccine in vaccinated mice sera compared to the control mice (in male and female mice were 12000±586 and 11566±642, respectively, p<0.001). Mechanistic analyses showed a significant reduction in serum PCSK9 concentrations by vaccine-induced antibodies in vaccine groups compared to the control groups (in male mice by 29±5 ng/mL (22.4%), p<0.001 and female mice by 26±5 ng / mL (21.0%), p<0.001). Serum concentrations of PCSK9 in control and vaccine groups were 131±8.6 ng / mL and 102±8.1 ng/ml in male mice and 124±6 ng/ml and 98±10 ng/ml in female mice, respectively. Moreover, vaccine-induced antibodies inhibited the PCSK9-LDLR interaction in male and female groups by 34% and 26%, respectively. No significant difference was detected between the male and female groups in all tests (p>0.05). CONCLUSION: According to our results, the PCSK9 peptide vaccine provoked the humoral immune system in albino mice to produce functional antibodies that inhibit plasma PCSK9. These effects were seen in both genders without any significant difference.

Compositional and functional properties of high-density lipoproteins in relation to coronary in-stent restenosis.

Introduction: In-stent restenosis (ISR) is an unfavorable outcome that occurs in patients after coronary stenting. Use of drugs such as statins as well as drug-eluting stents has only been partially effective in reducing the rate of ISR. Since low high-density lipoprotein cholesterol (HDL-C) concentration is a pivotal cardiovascular disease risk factor, this study aimed to evaluate the compositional and functional alterations of HDL in individuals with ISR. Material and methods: This case-control study included 21 ISR, 26 non-ISR (NISR), 16 angiography-negative, and 18 healthy subjects. Serum HDL2 (d: 1.063-1.125 g/ml) and HDL3 (d: 1.125-1.210 g/ml) subfractions were extracted from each subject using sequential ultracentrifugation. The capacity of HDL to efflux cellular cholesterol from lipid-loaded macrophages as well as to take up free cholesterol (FC) from triglyceride-rich lipoproteins (TGRLs) during lipolysis was assessed. Results: No difference was found in the HDL2 and HDL3 content of free cholesterol and total protein among the groups. The NISR group showed lower triglyceride content in HDL2 and higher phospholipid content in HDL3 relative to healthy subjects. Strong positive correlations were found between the cholesterol efflux capacity (CEC) of HDL2 and its phospholipid content in the healthy (r = 0.50), angiography-negative (r = 0.55) and ISR (r = 0.52) groups. The capacity of apolipoprotein B (apoB)-depleted serum to take up free cholesterol was not different among the groups. Conclusions: Despite some compositional alterations, the capacity of HDL to efflux cholesterol from lipid-loaded macrophages as well as to take up free cholesterol from TGRLs during lipolysis was not associated with ISR in this study.

Anti-arthritic and Antioxidant Effects of Trehalose in an Experimental Model of Arthritis.

BACKGROUND: The purpose of the present study was to study the potential anti-arthritic and antioxidant effects of trehalose in an experimental model of complete Freund's adjuvant (CFA)-induced arthritis. METHODS: Arthritis was induced via subcutaneous injection of CFA (0.1) into the right footpad of each rat. Trehalose (10 mg/kg per day) and indomethacin (5 mg/kg) as a reference drug were intraperitoneally injected into CFA-induced arthritic rats from days 0 to 21. Changes in paw volume, pain responses, arthritic score, and oxidative/antioxidative parameters were determined. RESULTS: Trehalose administration could significantly decrease arthritis scores (p <0.01) and paw edema (p <0.001), and significantly increase the nociceptive threshold (p <0.05) in CFA-induced arthritic rats. Trehalose also significantly reduced the pro-oxidant-antioxidant balance values when compared to CFA treatment alone. In addition, no significant difference was found between the trehalose group and indomethacin as a positive control group. CONCLUSION: The current study suggests that trehalose has a protective effect against arthritis, which may be mediated by antioxidative effects of this disaccharide.

An in vitro investigation of the effects of urolithins A and B on low-density lipoprotein uptake and its regulatory genes.

Introduction: This study aimed to evaluate the possible role of urolithin A (UA) and urolithin B (UB) on the mRNA expression levels of LDL receptor (LDLR) and PSCK9 genes, and also of the uptake of LDL particles in HepG2 cells. Material and methods: The potential role of UA and UB on the induction of LDL uptake and the expression of its regulatory genes was explored using HepG2 cells and curcumin (20 µM), berberine (50 µM), UA (80 µM), and UB (80 µM) as the treatments in the experimental tests. Results: The LDL uptake and cell-surface LDLR were higher in cells treated with UA in comparison with cells treated with UB, and even in relation to the cells treated with curcumin and berberine as positive controls. In addition, cells treated with UB showed approximately 2 times greater LDLR expression levels compared with curcumin (FC = 2.144, p = 0.013) and berberine (FC = 2.761, p = 0.006). However, UA treatment resulted in significantly lower expression levels of LDLR compared with curcumin (FC = 0.274, p < 0.001) and berberine (FC = 0.352, p = 0.009). UB demonstrated approximately 8 times higher LDLR expression levels when compared with UA (FC = 7.835, p = 0.001). Compared with UB, as well as curcumin and berberine as positive controls, UA was more efficient in reducing PCSK9 expression levels. Although UB did not show any significant differences compared with curcumin and berberine, it showed higher levels of PCSK9 expression when compared with the UA group (FC = 3.694, p < 0.001). Conclusions: The present results suggest that UA was more effective than UB in promoting LDL uptake as well as cell surface LDLR in HepG2 cells. This effect seems to be mostly mediated through the suppression of PCSK9 expression but not the induction of LDLR expression.

Differential Expression of miRNA-223 in Coronary In-Stent Restenosis.

OBJECTIVE: In-stent restenosis (ISR) is an unfavorable complication that occurs in patients after coronary stenting. Despite the progress with advent of modern DES and new antiplatelet agents, restenosis still hampers PCI short- and long-term results. The aim of this study was to investigate whether circulating miRNA-223, which is associated with HDL particles and involved in cholesterol efflux pathway, have diagnostic capability for determining ISR. METHODS: This case-control study comprised 21 ISR and 26 NISR patients. The level of miRNA-223 expression was evaluated by TaqMan Real-Time PCR, quantified by the comparative method (fold change) and normalized to U6 expression. RESULTS: Patients in ISR and NISR groups were not different in terms of demographic, clinical, and biochemical parameters, except that the percentage of patients who had DES was significantly greater in the NISR group (88.9%) in comparison with the ISR group (50%). The serum expression of miRNA-223 in ISR patients was 3.277 ± 0.9 times greater than that in NISR group (p = 0.016). In addition, the results of binary logistic regression demonstrated that the high level of serum miRNA-223 was strongly and positively associated with the ISR risk (OR: 17.818, 95% CI: 1.115-284.623, p = 0.042) after adjustment for age, sex, HDL-C, LDL-C, FBS, and statin consumption. CONCLUSION: Elevated serum level of miRNA-223 might be helpful in predicting the occurrence of ISR. Further confirmation in future large-scale studies is warranted.

Association between Oxidative Burden and Restenosis: A Case-Control Study.

Background: In-stent restenosis (ISR) is an important clinical complication that occurs following stent implantation. The application of drug-eluting stents (DES) and even consumption of drugs such as antiplatelet agents and statins are not completely effective in reducing ISR risk. Since the number of these patients continues to rise, it is pivotal to detect patients who are at a higher risk of ISR. In addition, identification of biochemical markers of ISR could give the right perspective on choosing the proper strategy to treat these patients. Several pathophysiological pathways including oxidative stress (OS) are implicated in the progression of ISR. Hence, this study aimed to evaluate the association between oxidative/anti-oxidative markers and ISR. Methods: This was a case-control study which comprised 21 ISR, 26 NISR (non-ISR), and 20 healthy subjects. The serum levels of OS markers including malondialdehyde (MDA), thiol groups (GSH), total antioxidant capacity (TAC), and the activity of serum antioxidant enzymes such as glutathione peroxidase (GPx) and superoxide dismutase (SOD) were assessed by colorimetric methods. The overall oxidative burden was assessed using a pro-oxidant-antioxidant balance (PAB) assay. Results: MDA levels were considerably higher in the ISR group when compared to healthy subjects (P = 0.004). PAB also indicated significantly higher values in both ISR (P < 0.001) and NISR (P < 0.001) groups related to healthy subjects. No significant differences were observed between the studied groups regarding thiol levels, antioxidant enzyme activities, and TAC. Multinomial logistic regression analysis showed that elevated serum levels of MDA (OR: 1.028, 95% CI: 1.008-1.048; P = 0.006) and PAB (OR: 1.076, 95% CI: 1.017-1.139; P = 0.011) were significantly associated with higher ISR risk; however, increased values of TAC (OR: 0.990, 95% CI: 0.982-0.999; P = 0.030) were significantly associated with decreased ISR risk, while after adjustment for confounders, only SOD activity (OR: 0.0, 95% CI: 0.0-0.0; P < 0.001) and PAB value (OR: 1.866, 95% CI: 1.856-1.900; P < 0.001) showed association with ISR risk. Conclusion: According to the present findings, some oxidative and antioxidative markers like PAB and SOD activity showed the potential in the prediction of ISR risk.