Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.

In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1WT), the LMS-causing Pro269Ser mutant (PSS1P269S), and PSS1WT in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4-8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System.

Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The "cholesterol shuttle" is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y2, P2X7 and A2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Niemann-Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol-purine reciprocal control could hopefully promote further research.

Novel Approach for Bone Marrow Transplantation Conditioning in Acute Myelogenous Leukemia not Responding to the Induction Therapy Using Etoposide Carried in Lipid Core Nanoparticles: A Pilot Clinical Study.

Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for acute myelogenous leukemia (AML) not responding to induction therapy. It is a therapeutic choice for the blast phase of chronic myelogenous leukemia (CML-BP) in patients failing to respond to tyrosine kinase inhibitors (TKIs). Lipid core nanoparticles (LDEs) concentrate severalfold more in blast cells than in corresponding normal cells. Incorporation of anticancer drugs to LDE formulations increases the pharmacologic action and decreases the toxicity. We tested a drug-targeting system, LDE-etoposide plus total body irradiation (TBI; 1200 cGy dose), in 13 patients with AML not responding to the induction therapy and in 2 patients with CML-BP refractory to second-generation TKIs. The mean patient age was 46.7 years (range, 22 to 66 years). The LDE-etoposide dose was escalated at 20, 30, 40, 50, and 60 mg/kg. No patients developed grade 4 or 5 toxicity; however, mucositis grade 3 occurred in 6 patients, 3 patients experienced diarrhea, and 1 patient had an elevated total bilirubin level. No deaths were related to conditioning. All patients were successfully engrafted. The median times to neutrophil and platelet engraftment were 20 ± 5 days and 16 ± 4 days, respectively. Five patients (33.4%) had acute graft-versus-host-disease (GVHD), including 4 grade I, and 1 with grade II, and 8 patients (57.1%) had moderate-to-severe chronic GVHD. This pilot study shows the potential of LDE-etoposide plus TBI as an HCT conditioning regimen in AML patients not responding to the induction and refractory therapies for CML-BP patient. These findings pave the way for subsequent larger clinical trials.

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism.

RATIONALE: The (pro)renin receptor ([P]RR) interacts with (pro)renin at concentrations that are >1000× higher than observed under (patho)physiological conditions. Recent studies have identified renin-angiotensin system-independent functions for (P)RR related to its association with the vacuolar H(+)-ATPase. OBJECTIVE: To uncover renin-angiotensin system-independent functions of the (P)RR. METHODS AND RESULTS: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins. This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density lipoprotein (LDL) receptor protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of epidermal growth factor or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDL receptor and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDL receptor induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1. CONCLUSIONS: Our study identifies a renin-angiotensin system-independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDL receptor.

The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL.

RATIONALE: The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance. OBJECTIVE: To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR. METHODS AND RESULTS: Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation. CONCLUSIONS: Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.

Two weeks of high-fat feeding disturb lipid and cholesterol molecular markers.

Metabolic disorders are often associated with liver steatosis and increased plasma cholesterol levels. However, the link between excessive lipid accumulation and impairments in cholesterol metabolism remains uninvestigated in the liver. Short term of high-fat diet (HFD) was previously shown to promote excessive lipid accumulation prior to the development of metabolic disorders. The present study intended to characterize how increases in liver fat alter the expression of several key regulators of hepatic cholesterol metabolism in response to a short-term HFD. Wistar rats were randomly submitted either to HFD (n = 8) or a regular chow diet (n = 8) for 14 days. Increases in triglycerides were highly significant (P < 0.01) in the liver but marginal in the plasma of HFD rats. In contrast, the HFD resulted in higher (P < 0.01) cholesterol levels in plasma but not in liver samples. Gene expression of key markers involved in cholesterol uptake (LDL particles) including low-density lipoprotein receptor-related protein-1 (LRP-1) and protein convertase subtilisin/kexin type 9 (PCSK9) along with ATP-binding cassette, superfamily G, member 5 (ABCG5) involved in cholesterol exportation via bile ducts was found to be higher (P < 0.05) in response to the HFD. In contrast, expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), involved in cholesterol synthesis, was downregulated in the liver. The data support the concept that excessive accumulation of lipids promptly alters the expression of key genes regulating cholesterol metabolism in the liver. On a clinical point of view, this indicates that increases in plasma cholesterol occur after a short-term HFD.

Activated α2 -Macroglobulin Induces Mesenchymal Cellular Migration Of Raw264.7 Cells Through Low-Density Lipoprotein Receptor-Related Protein 1.

Distinct modes of cell migration contribute to diverse types of cell movements. The mesenchymal mode is characterized by a multistep cycle of membrane protrusion, the formation of focal adhesion, and the stabilization at the leading edge associated with the degradation of extracellular matrix (ECM) components and with regulated extracellular proteolysis. Both α2 -Macroglobulin (α2 M) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1), play important roles in inflammatory processes, by controlling the extracellular activity of several proteases. The binding of the active form of α2 M (α2 M*) to LRP1 can also activate different signaling pathways in macrophages, thus inducing extracellular matrix metalloproteinase-9 (MMP-9) activation and cellular proliferation. In the present study, we investigated whether the α2 M*/LRP1 interaction induces cellular migration of the macrophage-derived cell line, Raw264.7. By using the wound-scratch migration assay and confocal microscopy, we demonstrate that α2 M* induces LRP1-mediated mesenchymal cellular migration. This migration exhibits the production of enlarged cellular protrusions, MT1-MMP distribution to these leading edge protrusions, actin polymerization, focal adhesion formation, and increased intracellular LRP1/ß1-integrin colocalization. Moreover, the presence of calphostin-C blocked the α2 M*-stimulated cellular protrusions, suggesting that the PKC activation is involved in the cellular motility of Raw264.7 cells. These findings could constitute a therapeutic target for inflammatory processes with deleterious consequences for human health, such as rheumatoid arthritis, atherosclerosis and cancer. J. Cell. Biochem. 118: 1810-1818, 2017. © 2016 Wiley Periodicals, Inc.

Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III.

BACKGROUND: The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS: Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). RESULTS: Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. CONCLUSIONS: Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.

The pharmacology of statins.

Statins, inhibitors of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme, are molecules of fungal origin. By inhibiting a key step in the sterol biosynthetic pathway statins are powerful cholesterol lowering medications and have provided outstanding contributions to the prevention of cardiovascular disease. Their detection in mycetes traces back to close to 40 years ago: there were, originally, widely opposing views on their therapeutic potential. From then on, intensive pharmaceutical development has led to the final availability in the clinic of seven statin molecules, characterized by differences in bioavailability, lipo/hydrophilicity, cytochrome P-450 mediated metabolism and cellular transport mechanisms. These differences are reflected in their relative power (mg LDL-cholesterol reduction per mg dose) and possibly in parenchymal or muscular toxicities. The impact of the antagonism of statins on a crucial step of intermediary metabolism leads, in fact, both to a reduction of cholesterol biosynthesis as well as to additional pharmacodynamic (so called "pleiotropic") effects. In the face of an extraordinary clinical success, the emergence of some side effects, e.g. raised incidence of diabetes and cataracts as well as frequent muscular side effects, have led to increasing concern by physicians. However, also in view of the present relatively low cost of these drugs, their impact on daily therapy of vascular patients is unlikely to change.

Host entry factors of Rift Valley Fever Virus infection.

Rift Valley Fever Virus (RVFV) is a negative sense segmented RNA virus that can cause severe hemorrhagic fever. The tri-segmented virus genome encodes for six (6) multifunctional proteins that engage host factors at a variety of different stages in the replication cycle. The S segment encodes nucleoprotein (N) and nonstructural protein S (NSs), the M segment encodes viral glycoproteins Gn and Gc as well as nonstructural protein M (NSm) and the L segment encodes the viral polymerase (L). Viral glycoproteins Gn and Gc are responsible for entry by binding to a number of host factors. Our recent studies identified a scavenger receptor, LDL receptor related protein 1 (Lrp1), as a potential pro-viral host factor for RVFV and related viruses, including Oropouche virus (OROV) infection. Coincidentally, several recent studies identified other LDL family proteins as viral entry factors and receptors for other viral families. Collectively, these observations suggest that highly conserved LDL family proteins may play a significant role in facilitating entry of viruses from several distinct families. Given the significant roles of viral and host factors during infection, characterization of these interactions is critical for therapeutic targeting with neutralizing antibodies and vaccines.

Amgen v. Sanofi: The U.S. Supreme Court Reviews Patent Enablement.

On June 18, 2023, the U.S. Supreme Court in the matter of Amgen, Inc. et al. v. Sanofi, et al.1 unanimously upheld the 2021 decision of the U.S. Court of Appeals for the Federal Circuit,2 striking down as overbroad Amgen's patent claim to an entire functional genus of monoclonal antibodies. Amgen's patent claims were not limited to antibody structure or antibody amino acid sequences. This is significant because Amgen's patent claims did have amino acid sequences, but they were directed to the epitope.

Individualized Treatment for Patients With Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common and, therefore, important inherited disorders in preventive cardiology. This disease is mainly caused by a single pathogenic mutation in the low-density lipoprotein receptor or its associated genes. Moreover, it is correlated with a high risk of cardiovascular disease. However, the phenotype severity even in this monogenic disease significantly varies. Thus, the current study aimed to describe FH and its importance and the factors (inherited and acquired) contributing to differences in phenotype severity. Different lipid-modification therapies according to these factors can lead to individualized treatments, which are also essential in the general populations.

Crocetin exerts hypocholesterolemic effect by inducing LDLR and inhibiting PCSK9 and Sortilin in HepG2 cells.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important post-transcriptional regulator of plasma levels of low-density lipoprotein cholesterol (LDL-C). Inhibition of PCSK9 has emerged as an attractive strategy in recent years to combat hypercholesterolemia stimulating the search for PCSK9 inhibitors. The carotenoid crocetin exhibits hypocholesterolemic effect. However, it is unknown whether the beneficial effect is mediated through PCSK9 modulation. We hypothesized that crocetin inhibits PCSK9 and therefore, in our quest for natural and safe PCSK9 inhibitors, we investigated crocetin on PCSK9 expression and other key molecular targets involved in hepatic cholesterol metabolism using the human hepatoma cell line HepG2 as a model system. We demonstrate for the first time that crocetin treatment significantly decreases PCSK9 and sterol regulatory element binding proteins (SREBP) expression in a dose-dependent manner, accompanied by a concomitant increase in the hepatic low-density lipoprotein receptor (LDLR) expression. Additionally, crocetin significantly downregulates the levels of both mRNA and protein expression of sortilin, a key sorting receptor that facilitates PCSK9 transport in the trans Golgi network in a dose dependent manner. Overall, our results suggest that crocetin is a LDLR inducer, and an inhibitor of PCSK9, sortilin and SREBPs, thus making it an effective natural anti-cholesterol agent.

Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia.

Cardiovascular disease (CVD) is the most common cause of death in a global scale and significantly depends on the elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and the subsequent formation of atherosclerotic plaques. While physicians have several LDL-C-lowering agents with diverse mechanisms of action, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran, angiopoietin-like protein 3 (ANGPTL3) inhibitors have recently emerged as a powerful addition in the armamentarium of lipid-lowering strategies, especially for patients with refractory hypercholesterolemia, as in the case of patients with homozygous familial hypercholesterolemia (HoFH). ANGPTL3 protein is a glycoprotein secreted by liver cells that is implicated in the metabolism of lipids along with other ANGPTL proteins. These proteins inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) in tissues. Loss-of-function mutations affecting the gene encoding ANGPTL3 are linked with lower total cholesterol, LDL-C, and triglyceride (TG) levels. Evinacumab is a monoclonal antibody that targets, binds to, and pharmacologically inhibits ANGPTL3, which was recently approved by the United States Food and Drug Administration (FDA) as a complementary agent to other LDL-C lowering regimens for patients aged 12 or older with HoFH, based on clinical trial evidence that confirmed its safety and efficacy in those patients. Antisense oligonucleotides (ASOs) also represent an interesting class of agents that target and inhibit the mRNA derived from the transcription of ANGPTL3 gene. This review aims to present and discuss the current clinical and scientific data pertaining to the role of ANGPTL3 inhibitors, a novel lipid-modifying class of agents capable of reducing LDL-C levels via a mechanism independent of LDL receptors.

TAFA4 relieves injury-induced mechanical hypersensitivity through LDL receptors and modulation of spinal A-type K+ current.

Pain, whether acute or persistent, is a serious medical problem worldwide. However, its management remains unsatisfactory, and new analgesic molecules are required. We show here that TAFA4 reverses inflammatory, postoperative, and spared nerve injury (SNI)-induced mechanical hypersensitivity in male and female mice. TAFA4 requires functional low-density lipoprotein receptor-related proteins (LRPs) because their inhibition by RAP (receptor-associated protein) dose-dependently abolishes its antihypersensitive actions. SNI selectively decreases A-type K+ current (IA) in spinal lamina II outer excitatory interneurons (L-IIo ExINs) and induces a concomitant increase in IA and decrease in hyperpolarization-activated current (Ih) in lamina II inner inhibitory interneurons (L-IIi InhINs). Remarkably, SNI-induced ion current alterations in both IN subtypes were rescued by TAFA4 in an LRP-dependent manner. We provide insights into the mechanism by which TAFA4 reverses injury-induced mechanical hypersensitivity by restoring normal spinal neuron activity and highlight the considerable potential of TAFA4 as a treatment for injury-induced mechanical pain.

Epigallocatechin Gallate Induces Upregulation of LDL Receptor via the 67 kDa Laminin Receptor-Independent Pathway in HepG2 Cells.

SCOPE: Epigallocatechin gallate (EGCG), an active polyphenol in green tea, exhibits various physiological effects, including activation of low-density lipoprotein receptors (LDLR). The previous studies have suggested that EGCG activates LDLR via extracellular signal-regulated kinase (ERK) pathway in HepG2 cells. However, the detailed molecular mechanism remains unclear. Recently, 67 kDa laminin receptor (67LR) is identified as a receptor for EGCG. Therefore, this study aims to determine whether 67LR is involved in the mechanism of LDLR activation by EGCG. METHODS AND RESULTS: EGCG induces upregulation of LDLR when 67LR is knocked down in HepG2 cells. Similar effect is observed after the cells are treated with 67LR monoclonal antibody. The loss of antiallergic effect following 67LR siRNA knockdown and 67LR antibody treatment confirms the results since the antiallergic effect of EGCG is known to be mediated by 67LR. CONCLUSION: EGCG activates LDLR expression via 67LR-independent pathway in HepG2 cells.

Lipoprotein receptor signalling in atherosclerosis.

The founding member of the lipoprotein receptor family, low-density lipoprotein receptor (LDLR) plays a major role in the atherogenesis through the receptor-mediated endocytosis of LDL particles and regulation of cholesterol homeostasis. Since the discovery of the LDLR, many other structurally and functionally related receptors have been identified, which include low-density lipoprotein receptor-related protein (LRP)1, LRP5, LRP6, very low-density lipoprotein receptor, and apolipoprotein E receptor 2. The scavenger receptor family members, on the other hand, constitute a family of pattern recognition proteins that are structurally diverse and recognize a wide array of ligands, including oxidized LDL. Among these are cluster of differentiation 36, scavenger receptor class B type I and lectin-like oxidized low-density lipoprotein receptor-1. In addition to the initially assigned role as a mediator of the uptake of macromolecules into the cell, a large number of studies in cultured cells and in in vivo animal models have revealed that these lipoprotein receptors participate in signal transduction to modulate cellular functions. This review highlights the signalling pathways by which these receptors influence the process of atherosclerosis development, focusing on their roles in the vascular cells, such as macrophages, endothelial cells, smooth muscle cells, and platelets. Human genetics of the receptors is also discussed to further provide the relevance to cardiovascular disease risks in humans. Further knowledge of the vascular biology of the lipoprotein receptors and their ligands will potentially enhance our ability to harness the mechanism to develop novel prophylactic and therapeutic strategies against cardiovascular diseases.

Suppression of abdominal fat and anti-hyperlipidemic potential of Emblica officinalis: Upregulation of PPARs and identification of active moiety.

Since ancient time, Emblica officinalis (E. officinalis) is being used for the management of various ailments. Phytochemical analysis proves that fruit juice of E. officinalis contains high amount gallic acid, which could be responsible for medicinal potentials. Hence in this study, gallic acid and fruit juice of E. officinalis were evaluated for anti-hyperlipidemic potential in various experimental animal models. Experimentally, hyperlipidemia was induced through administration of poloxamer-407, tyloxapol and high-fat-diet supplement in rats. Treatment with gallic acid as well as fruit juice of E. officinalis decreased plasma cholesterol and reduced oil infiltration in liver and aorta. Mechanistically, E. officinalis increased peroxisome proliferator-activated receptors-α (PPARα) expression and increased activity of lipid oxidation through carnitine palmitoyl transferase (CPT) along with decreased activity of hepatic lipogenic enzymes i.e. glucose-6-phosphate dehydrogenase (G6PD), fatty acid synthase (FAS) and malic enzyme (ME). Additionally, E. officinalis increased cholesterol uptake through increased LDL-receptor expressions on hepatocytes and decreased LDL-receptor degradation due to decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Simultaneously, E. officinalis showed ability to restore glucose homeostasis through increased Glut4 and PPARγ protein expression in adipose tissue. These findings exposed central role of gallic acid in E. officinalis arbitrated anti-hyperlipidemic action through upregulation of PPARs, Glut4 and lipogenic enzymes, and decreased expression of PCSK9 and lipogenic enzymes. Findings from this experiment demonstrated that E. officinalis is a potential therapy for management of hyperlipidemia and gallic acid could be a potential lead candidate.

Os Ácidos Graxos Poli-insaturados Ômega-6 e Ômega-3 Presentes nas Hemácias Exercem uma Influência Distinta sobre o Tamanho das Partículas de LDL e suas Alterações Estruturais / Red Blood Cells' Omega-6 and Omega-3 Polyunsaturated Fatty Acids Have a Distinct Influence on LDL Particle Size and its Structural Modifications

Resumo Fundamento Embora os ácidos graxos poli-insaturados ômega-3 e ômega-6 (AGPIs n-3 e n-6) tenham efeitos bem conhecidos sobre os fatores de risco de doenças cardiovasculares (DCV), ainda existe um conhecimento limitado sobre como eles afetam os indicadores de qualidade da LDL. Objetivo Avaliar as associações dos AGPIs n-3 e n-6 de hemácias com o tamanho da partícula da LDL, LDL-c pequena e densa (sdLDL-c) e com LDL eletronegativa [LDL(-)] em adultos com fatores de risco para DCV. Métodos Estudo transversal com 335 homens e mulheres de 30 a 74 anos com, pelo menos, um fator de risco cardiovascular. Foram realizadas análises de parâmetros bioquímicos, como glicose, insulina, HbA1c, proteína C reativa (PCR), perfil lipídico, subfrações de lipoproteínas, partícula eletronegativa de LDL [LDL(-)] e seu autoanticorpo, e os AGPIs n-3 e n- 6 de hemácias. Os testes t independente/teste de Mann-Whitney, ANOVA unidirecional/teste de Kruskal-Wallis e regressões lineares múltiplas foram aplicados. Todos os testes foram bilaterais e um valor de p inferior a 0,05 foi considerado estatisticamente significativo. Resultados A relação n-6/n-3 de hemácias foi associada ao aumento dos níveis de LDL(-) (β = 4,064; IC de 95% = 1,381 - 6,748) e sdLDL-c (β = 1,905; IC de 95% = 0,863 - 2,947), e redução do tamanho das partículas de LDL (β = -1,032; IC de 95% = -1,585 − -0,478). Individualmente, os AGPIs n-6 e n-3 apresentaram associações opostas com esses parâmetros, realçando os efeitos protetores do n-3 e evidenciando os possíveis efeitos adversos do n-6 na qualidade das partículas de LDL. Conclusão O AGPI n-6, presente nas hemácias, foi associado ao aumento do risco cardiometabólico e à aterogenicidade das partículas de LDL, enquanto o AGPI n-3 foi associado a melhores parâmetros cardiometabólicos e à qualidade das partículas de LDL.

Abstract Background While Omega-3 and omega-6 polyunsaturated fatty acids (n-3 and n-6 PUFAs) have established effects on cardiovascular disease (CVD) risk factors, little is known about their impacts on LDL quality markers. Objective To assess the associations of n-3 and n-6 PUFA within red blood cells (RBC) with LDL particle size, small dense LDL-c (sdLDL-c), and electronegative LDL [LDL(-)] in adults with CVD risk factors. Methods Cross-sectional study involving 335 men and women aged 30 to 74 with at least one cardiovascular risk factor. Analyses were conducted on biochemical parameters, such as glucose, insulin, HbA1c, C-reactive protein (CRP), lipid profile, lipoprotein subfractions, electronegative LDL particle [LDL(-)] and its autoantibody, and RBC n-3 and n-6 PUFAs. Independent t-test/Mann-Whitney test, one-way ANOVA/Kruskal-Wallis test, and multiple linear regressions were applied. All tests were two-sided, and a p-value of less than 0.05 was considered statistically significant. Results The RBC n-6/n-3 ratio was associated with increased LDL(-) (β = 4.064; 95% CI = 1.381 - 6.748) and sdLDL-c (β = 1.905; 95% CI = 0.863 - 2.947) levels, and reduced LDL particle size (β = -1.032; 95% CI = -1.585 − -0.478). Separately, n-6 and n-3 PUFAs had opposing associations with those parameters, reinforcing the protective effects of n-3 and showing the potential negative effects of n-6 on LDL particle quality. Conclusion RBC n-6 PUFA was associated with increased cardiometabolic risk and atherogenicity of LDL particles, while n-3 PUFA was associated with better cardiometabolic parameters and LDL particle quality.

Clinical experience with drug delivery systems as tools to decrease the toxicity of anticancer chemotherapeutic agents.

INTRODUCTION: The toxicity of chemotherapeutic agents, resulting from their low pharmacological index, introduces considerable discomfort and risk to cancer patients. Among several strategies to reduce the toxicity of chemotherapeutic agents, targeted drug delivery is the most promising one. Areas covered: Liposomes, micelles, albumin-based, polymeric, dendritic and lipid core nanoparticles have been used as carriers to concentrate anticancer drugs in neoplastic tissues, and clinical studies of those preparations are reviewed. In most clinical studies, drug delivery systems reduced drug toxicity. Lipid core nanoparticles (LDE) that bind to cell lipoprotein receptors have the ability to concentrate in neoplastic tissues and were the first artificial non-liposomal system shown in in vivo studies to possess targeting properties. The toxicity reduction achieved by LDE as vehicle of carmustine, etoposide and paclitaxel was singularly strong. Expert opinion: The reduced toxicity offered by drug delivery systems has expanded treatment population that may benefit from chemotherapy including feeble, overtreated and elderly patients that would otherwise be offered palliative therapy. Drug delivery systems may either prolong the duration of treatments or allow increases in drug dose.