👤 A Sahebkar

Elevated levels of lipoprotein(a) [Lp(a)] are increasingly recognized as an independent risk factor for cardiovascular diseases (CVDs). This systematic review and meta-analysis aimed to evaluate the impact of lipid apheresis therapy on serum Lp(a) levels in a wide array of disorders, particularly CVDs. Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science databases up to May 2025. Studies reporting pre- and post-treatment Lp(a) levels in participants undergoing lipid apheresis were included. A random-effects model was used when heterogeneity was significant. Subgroup and meta-regression analyses were conducted to explore potential sources of heterogeneity. A total of 43 publications comprising 67 studies with 2466 participants were analysed. Lipid apheresis significantly reduced serum Lp(a) levels (SMD = -1.52; 95% CI = -1.76 to -1.29; P < 0.001). Subgroup analyses confirmed significant reductions across various methods of Lp(a) detection, disease backgrounds, and initial Lp(a) levels. One-session lipid apheresis studies (n = 6) also demonstrated a significant reduction (SMD = -1.51; 95% CI = -1.72 to -1.29; P < 0.001). Meta-regression suggested that publication year and disease background contributed to heterogeneity. Lipid apheresis is effective in significantly lowering serum Lp(a) concentrations across a range of patient groups and treatment modalities. These findings support the therapeutic role of lipid apheresis in managing elevated Lp(a). Show less

Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of early atherosclerosis-related cardiovascular disease. This review discusses the genetics, epidemiology, diagnosis, and novel therapeutic approaches for FH. Mutations in the LDL receptor gene are the primary cause of FH. Less common causes include mutations in proprotein convertase subtilisin/kexin type 9 and apolipoprotein B-100. In extremely rare cases, LDLR adaptor protein 1 mutations can also cause FH. Epidemiological data indicate that FH is frequently underdiagnosed, particularly within certain ethnic populations. Diagnostic criteria often rely on clinical manifestations and family history, although genetic testing is increasingly advocated for confirmation. Recent advancements in pharmacotherapy offer substantial opportunities for effective low-density lipoprotein cholesterol control and management of FH, providing new hope for affected patients. This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin. However, some of these newer agents are specifically designed to lower elevated Lp(a), which often occurs in patients with FH, and triglycerides. Furthermore, gene-editing approaches, such as clustered regularly interspaced short palindromic repeats -Cas9 and meganuclease, as well as vaccines targeting key components of cholesterol metabolism, represent promising future directions for FH treatment. SIGNIFICANCE STATEMENT: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels, which increase the risk of atherosclerotic cardiovascular disease. Conventional therapies, such as statins, often have limited efficacy in patients with FH. Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment. Show less

Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes mellitus and a leading cause of end-stage renal disease worldwide. Although hyperglycemia and hypertension are well-established drivers of DKD, accumulating evidence suggests that additional factors, such as lipoprotein(a) [Lp(a)], may contribute to its pathogenesis. Lp(a) is a genetically determined lipoprotein with pro-atherogenic, pro-inflammatory, and pro-thrombotic properties, and elevated circulating levels have been associated with increased cardiovascular and renal risk in diabetic individuals. In this review, we summarize the current understanding of the relationship between Lp(a) and DKD, with a focus on the proposed molecular mechanisms. These include activation of TGF-β/Smad signaling leading to fibrosis, induction of oxidative stress, chronic inflammation, endothelial dysfunction, impaired fibrinolysis, and direct injury to podocytes resulting in proteinuria. While several clinical and experimental studies support the involvement of Lp(a) in these pathways, the precise molecular mediators remain largely undefined. Understanding these mechanisms may offer novel insights into the pathophysiology of DKD and identify new therapeutic targets. This article aims to provide a comprehensive overview of the potential role of Lp(a) in DKD and to highlight areas requiring further investigation. Show less

This review examines the physiological functions of Angiopoietin-like proteins (ANGPTLs) in lipid metabolism and the epidemiology of atherosclerotic cardiovascular disease (ASCVD), while discussing their potential as therapies for dyslipidemias. A review of contemporary literature on ANGPTLs was conducted. ANGPTLs comprise eight secreted proteins that share structural similarities with the angiopoietin family and serve as key regulators of various physiological and biochemical functions. Notably, ANGPTL3, ANGPTL4, and ANGPTL8 act as physiological inhibitors of lipoprotein lipase (LPL), playing a crucial role in lipoprotein and triglyceride metabolism in response to the body's nutritional status. A deficiency in these proteins is linked to hypolipidemia, characterized by a decrease in all lipid fractions, and genetic studies indicate a reduced risk of ASCVD in individuals with loss-of-function variants in ANGPTL3 and ANGPTL4. Conversely, elevated levels of ANGPTL3, ANGPTL4, and ANGPTL8 seem to increase the risk of cardiovascular disease. The role of ANGPTLs in regulating lipid metabolism underscores their potential in targeted therapies for managing dyslipidemias and lowering ASCVD risk, particularly in patients with difficult-to-control dyslipidemia phenotypes, such as homozygous Familial Hypercholesterolemia and mixed dyslipidemia. The development of ANGPTL inhibitors could provide an effective strategy for preventing ASCVD. Show less

Apolipoprotein-A4 (Apo-A4) is a plasma protein that plays a role in various physiological and behavioral-emotional reactions when faced with stress. Studies have shown a close relationship between Apo-A4 and the onset of depression and its symptoms. However, there is currently no reliable laboratory approach to confirm the diagnosis of depression. Therefore, the development of a precise and effective technique to assess Apo-A4 might help in the early detection and screening of depression and other related psychiatric diseases, as well as in tracking and managing the course of treatment. As technology advances, biosensors have become quick, accurate, and sensitive tools for personal care and illness diagnosis. Biosensors for measuring and detecting Apo-A4 levels have recently been designed. These studies emphasized the development of accurate and sensitive diagnostic and measurement techniques. This review attempts to give a general overview of the role of Apo-A4 in depression and introduce established biosensors for its detection and measurement. Show less

In the last decades, the biological properties of Lp(a) have attracted increasing attention for their possible involvement in a wide range of clinical conditions other than atherosclerotic cardiovascular disease. To date, whether a pathogenic interplay may exist between Lp(a) and cancer remains unclear. Indeed, experimental studies mainly show a protective effect of Lp(a) toward cancer, while results of clinical studies are highly contradictory. Nonetheless, the confirmation of any link between Lp(a) metabolism and cancer may be highly impactful for its translational implications in the current era of a renewed scientific interest in this lipoprotein. Indeed, the increasing availability of laboratory assays for the routine assessment of plasma Lp(a) levels could be proposed as an additional tool for cancer diagnosis and prognostic stratification. In addition, the tumultuous development of anti-Lp(a) therapeutics, if a pro-cancerogenic Lp(a) activity will be confirmed, could have an impact on the natural history of cancer and on its pharmacological management. This review resumes current knowledge on the relationship between Lp(a) and cancer as well as on its possible impact on the oncological field. Show less

To evaluate the effect of pioglitazone, a member of the thiazolidinedione family of drugs known for its antihyperglycemic properties, on lipoprotein (a) [Lp(a)]. Pioglitazone is recognized for enhancing insulin sensitivity and β-cell function, and it also has a positive influence on the overall lipid profile. Meta-analysis of 7 studies (4 RCTs and three non-RCTs) including 254 patients showed a significant decrease of circulating Lp(a) levels after treatment with pioglitazone (SMD: -0.373, 95% CI: -0.642, -0.104, p = 0.007). The reduction in circulating Lp(a) was robust in the leave-one-out sensitivity analysis. The presented results were obtained following a comprehensive literature search conducted in PubMed, Scopus, Embase, and Web of Science, covering studies from their inception up to March 1, 2025. Pioglitazone significantly decreases circulating Lp(a) concentrations. This decrease might have a beneficial effect on atherosclerotic cardiovascular disease (ASCVD) in high-risk patients. Show less

Atherosclerosis is a chronic inflammatory disease in which aberrant lipid metabolism plays a key role. MicroRNAs (miRNAs), micro-coordinators of gene expression, have been recently proposed as novel clinical biomarkers and potential therapeutic tools for a broad spectrum of diseases. This study aimed to identify miRNAs with therapeutic potential in atherosclerosis. Bioinformatic databases, including experimentally validated and computational prediction tools as well as a novel combination method, were used to identify miRNAs that are able to simultaneously inhibit key genes related to the pathogenesis of atherosclerosis. Further validation of genes and miRNAs was conducted using the STRING online tool, KEGG pathway analysis and DIANA-miRPath. The inhibitory effects of the identified miRNAs in HepG2 and Huh7 cells were verified by real-time PCR. The MTT assay was utilized to evaluate cell cytotoxicity effects of miRNAs. Atherosclerotic drug-targeted genes were selected as key genes. Strong interactions between genes were confirmed using STRING. These genes were shown to be integral to critical pathological processes involved in atherosclerosis. A novel combined method of validated and predicted tools for the identification of effective miRNAs was defined as the combination score (C-Score). Bioinformatic analysis showed that hsa-miR-124-3p and hsa-miR-16-5p possessed the best C-Score (0.68 and 0.62, respectively). KEGG and DIANA-miRPath analysis showed that selected genes and identified miRNAs were involved in atherosclerosis-related pathways. Compared with the controls in both HepG2 and Huh7 cell lines, miR-124 significantly reduced the expression of CETP, PCSK9, MTTP, and APOB, and miR-16 significantly reduced the expression of APOCIII, CETP, HMGCR, PCSK9, MTTP, and APOB, respectively. The cytotoxicity assay showed that miR-124 reduced cell viability, especially after 72 h; however, miR-16 did not show any significant cytotoxicity in either cell line. Our findings indicate that hsa-miR-124 and miR-16 have potential for use as therapeutic candidates in the treatment of atherosclerosis. Show less

Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPAR We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD. Show less

Breast cancer is one of the main challenging areas in cancer treatment. Natural compounds such as curcumin and berberine have been approved with anticancer effects and are more favorable to people. Here, we investigated the potential synergistic anticancer effects of these two compounds in combination with the standard cancer drug 5-FU on the growth of MCF-7 breast cancer cells. This study tested the effects of six different treatments on cancer cell growth: A) control; B) curcumin; C) berberine; D) 5-FU; E) curcumin + berberine; and F) curcumin + berberine + 5-FU. The IC There was a reduction in cancer cell growth and invasion, and an increase in cellular decomposition across all treatment groups compared to the control with the strongest effects seen in the combined curcumin/berberine/5-FU group. The expression levels of all tested genes were altered in all treatment groups compared to the control, with that of WNT1, CTNNB1, TCF, MTOR, AKT1, BIRC5, and CCND1 showing the most robust changes in the combined curcumin/berberine/5-FU treatment. All treatment groups had anti-growth, anti-invasion, and pro-apoptotic effects on MCF-7 breast cancer cells in culture. In addition, all treatment groups showed changes in the expression of the genes involved in cancer cell growth and survival with the strongest effects found for the curcumin/berberine/5-FU combination. Therefore, curcumin and berberine may improve the anticancer effects of chemotherapy and these natural compounds should undergo further testing as potential adjuvants. Show less

Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl ester from HDL-C to LDL-C and VLDL-C. The aim of the present trial was to evaluate the effect of curcumin and its modified formulation on serum CETP concentrations in patients with metabolic syndrome. Participants were randomly allocated to one of three groups of 40 subjects receiving either unmodified curcumin or its phospholipid complex or placebo. Lipid profile and plasma CETP were measured at the start and six weeks after initiation of the treatment. The normality of data distribution was assessed by Kolmogorov-Smirnov test. Wilcoxon test was used for comparing the data before and after the intervention. The percent changes of CETP and biochemical factors among the three groups were compared using Kruskal-Wallis test. Serum CETP levels were not significantly altered among patients receiving curcumin. Curcumin and its complex had no significant effect on serum CETP concentrations. Show less

Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk. Moreover, there is compelling evidence on the presence of still considerable residual cardiovascular risk in statin-treated patients. Ezetimibe improves cholesterol-lowering efficacy and provides mild additional cardiovascular protection when combined with statin treatment. Despite a favorable safety profile compared to statins, ezetimibe-induced cholesterol-lowering is modest when used alone. Hence, there is a critical need to identity additional effective hypolipidemic agents that can be used either in combination with statins, or alone, if statins are not tolerated. Thus, hypolipidemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors, as well as yeast polysaccharides (beta-glucans and mannans) and compounds derived from natural sources (nutraceuticals) such as glucomannans, plant sterols, berberine, and red yeast rice are being used. In this review, we will discuss hypercholesterolemia, its impact on the development of cardiovascular disease (CVD), and the use of yeast polysaccharides, various nutraceuticals, and several therapeutic agents not derived from 'natural' sources, to treat hypercholesterolemia. Show less

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. Show less