Explore the vast range of titles available.

The pathogenesis and progression of atherosclerosis are integrally connected to the concentration and function of lipoproteins in various classes. This review examines existing and emerging approaches to modify low‐density lipoprotein and lipoprotein (a), triglyceride‐rich lipoproteins, and high‐density lipoproteins, emphasizing approaches that have progressed to clinical evaluation. Targeting of nuclear receptors and phospholipases is also discussed. Graphical Abstract This review article summarizes existing and emerging therapeutic strategies to modify all types of lipoproteins, whose concentration and function are critical in the progression of atherosclerosis.

Lipoprotein(a) is similar to LDL cholesterol but contains apolipoprotein(a). A trial tested the effects of an oligonucleotide drug targeting apo(a) mRNA on lipoprotein(a) concentrations in patients with CVD.

Elevated lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease. The safety and efficacy of lepodisiran, an extended-duration, small interfering RNA targeting hepatic synthesis of lipoprotein(a), are unknown. We randomly assigned participants in a 1:2:2:2:2 ratio to receive lepodisiran at a dose of 16 mg, 96 mg, or 400 mg at baseline and again at day 180, lepodisiran at a dose of 400 mg at baseline and placebo at day 180, or placebo at baseline and at day 180, all administered by subcutaneous injection. Data from the two groups that received lepodisiran at a dose of 400 mg at baseline were pooled for the primary analysis. The primary end point was the time-averaged percent change from baseline in the serum lipoprotein(a) concentration (lepodisiran difference from placebo [i.e., placebo-adjusted]) during the period from day 60 to day 180. A total of 320 participants underwent randomization; the median baseline lipoprotein(a) concentration was 253.9 nmol per liter. The placebo-adjusted time-averaged percent change from baseline in the serum lipoprotein(a) concentration from day 60 to day 180 was -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups. The corresponding change from day 30 to day 360 was -41.2 percentage points (95% CI, -55.4 to -22.4), -77.2 percentage points (95% CI, -81.8 to -71.5), -88.5 percentage points (95% CI, -90.8 to -85.6), and -94.8 percentage points (95% CI, -95.9 to -93.4) in the 16-mg, 96-mg, 400-mg-placebo, and 400-mg-400-mg dose groups, respectively. Serious adverse events, none of which were deemed by investigators to be related to lepodisiran or placebo, occurred in 35 participants. Dose-dependent, generally mild injection-site reactions occurred in up to 12% (8 of 69) of the participants in the highest lepodisiran dose group. Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration. (Funded by Eli Lilly; ALPACA ClinicalTrials.gov number, NCT05565742.).

Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump. Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.

Background Epidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized. Methods We performed nuclear magnetic resonance (NMR) metabolomics on plasma samples derived from 30 individuals with elevated Lp(a) (> 150 mg/dL). The 30 participants were randomly assigned into two groups, placebo ( N  = 14) and evolocumab ( N  = 16). We assessed the effect of 16 weeks of evolocumab 420 mg Q4W treatment on circulating metabolites by running lognormal regression analyses, and compared this to placebo. Subsequently, we assessed the interrelationship between Lp(a) and 14 lipoprotein subclasses in response to treatment with evolocumab, by running multilevel multivariate regression analyses. Results On average, evolocumab treatment for 16 weeks resulted in a 17% (95% credible interval: 8 to 26%, P  < 0.001) reduction of circulating Lp(a), coupled with substantial reduction of VLDL, IDL and LDL particles as well as their lipid contents. Interestingly, increasing concentrations of baseline Lp(a) were associated with larger reduction in triglyceride-rich VLDL particles after evolocumab treatment. Conclusions Inhibition of PCSK9 with evolocumab markedly reduced VLDL particle concentrations in addition to lowering LDL-C. The extent of reduction in VLDL particles depended on the baseline level of Lp(a). Our findings suggest a marked effect of evolocumab on VLDL metabolism in subjects with elevated Lp(a). Trial registration Clinical trial registration information is registered at ClinicalTrials.gov on April 14, 2016 with the registration number NCT02729025 .

Altered lipid metabolism has been shown in fish fed plant protein sources. The present study aimed to gain further insights into how intestinal and hepatic lipid absorption and metabolism are modulated by plant meal (PM) and soya-saponin (SA) inclusion in salmon feed. Post-smolt Atlantic salmon were fed for 10 weeks one of four diets based on fishmeal or PM, with or without 10 g/kg SA. PM inclusion resulted in decreased growth performance, excessive lipid droplet accumulation in the pyloric caeca and liver, and reduced plasma cholesterol levels. Intestinal and hepatic gene expression profiling revealed an up-regulation of the expression of genes involved in lipid absorption and lipoprotein (LP) synthesis (apo, fatty acid transporters, microsomal TAG transfer protein, acyl-CoA cholesterol acyltransferase, choline kinase and choline-phosphate cytidylyltransferase A), cholesterol synthesis (3-hydroxy-3-methylglutaryl-CoA reductase) and associated transcription factors (sterol regulatory element-binding protein 2 and PPARγ). SA inclusion resulted in reduced body pools of cholesterol and bile salts. The hepatic gene expression of the rate-limiting enzyme in bile acid biosynthesis (cytochrome P450 7A1 (cyp7a1)) as well as the transcription factor liver X receptor and the bile acid transporter abcb11 (ATP-binding cassette B11) was down-regulated by SA inclusion. A significant interaction was observed between PM inclusion and SA inclusion for plasma cholesterol levels. In conclusion, gene expression profiling suggested that the capacity for LP assembly and cholesterol synthesis was up-regulated by PM exposure, probably as a compensatory mechanism for excessive lipid droplet accumulation and reduced plasma cholesterol levels. SA inclusion had hypocholesterolaemic effects on Atlantic salmon, accompanied by decreased bile salt metabolism.

Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of around 10,000 different soluble and membrane proteins in humans. It involves the co- or post-translational targeting of precursor polypeptides to the ER, and their subsequent membrane insertion or translocation. So far, three pathways for the ER targeting of precursor polypeptides and four pathways for the ER targeting of mRNAs have been described. Typically, these pathways deliver their substrates to the Sec61 polypeptide-conducting channel in the ER membrane. Next, the precursor polypeptides are inserted into the ER membrane or translocated into the ER lumen, which may involve auxiliary translocation components, such as the TRAP and Sec62/Sec63 complexes, or auxiliary membrane protein insertases, such as EMC and the TMCO1 complex. Recently, the PEX19/PEX3-dependent pathway, which has a well-known function in targeting and inserting various peroxisomal membrane proteins into pre-existent peroxisomal membranes, was also found to act in the targeting and, putatively, insertion of monotopic hairpin proteins into the ER. These either remain in the ER as resident ER membrane proteins, or are pinched off from the ER as components of new lipid droplets. Therefore, the question arose as to whether this pathway may play a more general role in ER protein targeting, i.e., whether it represents a fourth pathway for the ER targeting of precursor polypeptides. Thus, we addressed the client spectrum of the PEX19/PEX3-dependent pathway in both PEX3-depleted HeLa cells and PEX3-deficient Zellweger patient fibroblasts by an established approach which involved the label-free quantitative mass spectrometry of the total proteome of depleted or deficient cells, as well as differential protein abundance analysis. The negatively affected proteins included twelve peroxisomal proteins and two hairpin proteins of the ER, thus confirming two previously identified classes of putative PEX19/PEX3 clients in human cells. Interestingly, fourteen collagen-related proteins with signal peptides or N-terminal transmembrane helices belonging to the secretory pathway were also negatively affected by PEX3 deficiency, which may suggest compromised collagen biogenesis as a hitherto-unknown contributor to organ failures in the respective Zellweger patients.

Sepsis, a life-threatening syndrome with increasing incidence worldwide, is triggered by an overwhelming inflammation induced by microbial toxins released into the bloodstream during infection. A well-known sepsis-inducing factor is the membrane constituent of Gram-negative bacteria, lipopolysaccharide (LPS), signalling via Toll-like receptor-4. Although sepsis is caused in more than 50% cases by Gram-positive and mycoplasma cells, the causative compounds are still poorly described. In contradicting investigations lipoproteins/-peptides (LP), lipoteichoic acids (LTA) and peptidoglycans (PGN), were made responsible for eliciting this pathology. Here, we used human mononuclear cells from healthy donors to determine the cytokine-inducing activity of various LPs from different bacterial origin, synthetic and natural and compared their activity with that of natural LTA and PGN. We demonstrate that LP are the most potent non-LPS pro-inflammatory toxins of the bacterial cell walls, signalling via Toll-like receptor-2, not only in vitro , but also when inoculated into mice: A synthetic LP caused sepsis-related pathological symptoms in a dose-response manner. Additionally, these mice produced pro-inflammatory cytokines characteristic of a septic reaction. Importantly, the recently designed polypeptide Aspidasept ® which has been proven to efficiently neutralize LPS in vivo , inhibited cytokines induced by the various non-LPS compounds protecting animals from the pro-inflammatory activity of synthetic LP.

Spiroplasma poulsonii is a maternally transmitted bacterial endosymbiont that is naturally associated with Drosophila melanogaster. S. poulsonii resides extracellularly in the hemolymph, where it must acquire metabolites to sustain proliferation. In this study, we find that Spiroplasma proliferation specifically depletes host hemolymph diacylglyceride, the major lipid class transported by the lipoprotein, Lpp. RNAi-mediated knockdown of Lpp expression, which reduces the amount of circulating lipids, inhibits Spiroplasma proliferation demonstrating that bacterial proliferation requires hemolymph-lipids. Altogether, our study shows that an insect endosymbiont acquires specific lipidic metabolites from the transport lipoproteins in the hemolymph of its host. In addition, we show that the proliferation of this endosymbiont is limited by the availability of hemolymph lipids. This feature could limit endosymbiont over-proliferation under conditions of host nutrient limitation as lipid availability is strongly influenced by the nutritional state. All animals host a large number of harmless microbes. Often the two partners involved in these interactions will depend on each other to thrive: microbes support important host functions and in return the host provides a safe place to live and a continuous supply of food. Many microbes that are intimately associated with animals have lost the ability to gain nutrients from sources other than their host and are unable to survive on their own. However, in many cases, the source and the type of nutrients provided to the microbes are unknown. One of the most common microbial species found in insects is Spiroplasma. This microbe lives in very large numbers in the fluid that fills the body cavities of insects, called the hemolymph. The microbes are transmitted from mother to offspring, and in some circumstances can provide benefits to the insects; for instance, Spiroplasma-infested flies appear to be protected against infection by some parasites. Unfortunately, as it is difficult to study insect–microbe relationships, little else is known about the physiological interactions between these two species. Herren et al. studied the association between Spiroplasma and the fly Drosophila melanogaster. Under normal conditions, Spiroplasma only reduces the life span of the infested fly. This indicates that Spiroplasma has a low impact on the general fitness of its host, only negatively affecting the survival and egg laying ability of old flies. When flies had limited access to nutrients, the number of Spiroplasma they carried was reduced, without the flies losing fitness. This suggests that Spiroplasma growth is dependent on something in the flies' diet. To understand which nutrients are important for the growth of Spiroplasma in Drosophila, Herren et al. analyzed the hemolymph of flies and found that there are fewer fatty-molecules, called lipids, when nutrients are limited. Healthy flies carrying Spiroplasma also have fewer lipids in their hemolymph, suggesting that these are what Spiroplasma feed on. Indeed, inactivating a protein required by the fly to transport lipids to the hemolymph reduced the growth of Spiroplasma in these flies. Herren et al. concluded that the growth of Spiroplasma inside its host is limited by the availability of lipids in the hemolymph. Since this is dependent on diet, the dependence on lipids couples the growth of Spiroplasma to the nutritional state of its host. Herren et al. speculate that this mechanism reduces the fitness cost of harboring the microbes and prevents the damaging consequence of an uncontrolled proliferation of the microbes. Moreover, Spiroplasma's preference for lipids may explain why it helps to protect flies against parasitic infection, as many parasites also rely on lipids for their growth. Herren et al. suggest this strategy could also be used in other animal–microbe associations.

Replacement therapy with missing factor (F) VIII or IX in haemophilia patients for bleed management and preventative treatment or prophylaxis is standard of care. Restoration of thrombin generation through novel mechanisms has become the focus of innovation to overcome limitations imposed by protein replacement therapy. Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor (TF)-induced coagulation through a FXa-dependent feedback inhibition of the TF.FVIIa complex in plasma and on endothelial surfaces. Concizumab is a monoclonal, humanised antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit haemophilia model. Phase 1 single and multiple dose escalation studies in haemophilia patients demonstrated a dose dependent decrease in TFPI levels and a pro-coagulant effect with increasing d-dimers and prothrombin fragment 1 + 2. A dose dependent increase in peak thrombin and endogenous thrombin potential was observed with values in the normal range when plasma TFPI levels were nearly undetectable. A few haemophilia patients in the highest dose cohorts with complete inhibition of plasma TFPI showed a decreased fibrinogen concentration with normal levels of anti-thrombin and platelets and no evidence of thrombosis. Pharmacokinetic parameters were influenced by binding to the target (TFPI), demonstrating target mediated drug disposition. A trend towards decreasing bleeding tendency was observed and this preventative effect is being studied in Phase 2 studies with additional data gathered to improve our understanding of the therapeutic window and potential for thrombosis.