Explore the vast range of titles available.

Hyperlipidemia is a medical condition characterized by an increase in one or more of the plasma lipids, including triglycerides, cholesterol, cholesterol esters, phospholipids and or plasma lipoproteins including very low-density lipoprotein and low-density lipoprotein along with reduced high-density lipoprotein levels. This elevation of plasma lipids is among the leading risk factors associated with cardiovascular diseases. In the meantime, statins and fibrates remain the major anti-hyperlipidemic agents for the treatment of elevated plasma cholesterol and triglycerides respectively, with the price of severe side effects on the muscles and the liver. The present review focuses mainly on the types of hyperlipidemias, lipid metabolism, treatments and new drug targets for the treatment of elevated lipid profile. Many agents such as lanosterol synthase inhibitors, squalene epoxidase inhibitors, diacyl glycerol acyl transferase inhibitors, ATP citrate lyase inhibitors have shown a promising potential in the treatment of hyperlipidemia in clinical trials.

Cardiovascular diseases (CVD) are the major cause of death among people across the globe.  Hypercholesterolemia is one of the major contributing factors for CVD. Molecules that bind with Lanosterol synthase enzyme, can be potential drug targets.  Statin group of compounds like Simvastatin, cerivastatin, Atorvastatin etc., used for treating hypercholesterolemia have side effects and hence there is a growing demand for plant derived flavonoids.  This work focusses on studying the compounds quercetin-3-O-(2??,6??-di-O-?-l-rhamnopyranosyl)-?-d-glucopyranoside, kaempferol-3-O-(2??,6??-di-O-?-l-rhamnopyranosyl)-?-d-glucopyranoside, rutin; quercetin-3-O-?-d-glucopyranoside (Iso quercetin); and kaempferol-3-O-?-d-glucopyranoside (Astragalin) present in Chenopodium album Linn to inhibit Lanosterol synthase.   Bioactivity score, drug likeness character was assessed in silico.  Based on bioactivity spectrum, it is observed that the molecules are biologically active and the probability of these compounds to be biologically active is ranging from 0.784 to 0.992, suggesting that these compounds are effective for treating hypercholesterolemia.   In the molecular docking studies, the compounds binding affinity score was in agreement that the molecules have the potential to be used as an alternative to the statin group of compounds in treating cholesterol.

Soft-bodied slow-moving sea creatures such as sea stars and sea cucumbers lack an adaptive immune system and have instead evolved the ability to make specialized protective chemicals (glycosylated steroids and triterpenes) as part of their innate immune system. This raises the intriguing question of how these biosynthetic pathways have evolved. Sea star saponins are steroidal, while those of the sea cucumber are triterpenoid. Sterol biosynthesis in animals involves cyclization of 2,3-oxidosqualene to lanosterol by the oxidosqualene cyclase (OSC) enzyme lanosterol synthase (LSS). Here we show that sea cucumbers lack LSS and instead have two divergent OSCs that produce triterpene saponins and that are likely to have evolved from an ancestral LSS by gene duplication and neofunctionalization. We further show that sea cucumbers make alternate sterols that confer protection against self-poisoning by their own saponins. Collectively, these events have enabled sea cucumbers to evolve the ability to produce saponins and saponin-resistant sterols concomitantly.Sea stars and sea cucumbers biosynthesize protective glycosylated steroids and triterpenes via divergent oxidosqualene cyclases (OSCs) that produce these distinct saponins in different species as well as in different tissues of a single species.

Decadal glacier thickness changes over the Upper Indus Basin in the Jammu and Kashmir Himalaya were estimated using the TanDEM-X and SRTM-C Digital Elevation Models (DEMs) from 2000 to 2012. In the study area 12,243 glaciers having 19,727 ± 1,054 km 2 area have thinned on an average of − 0.35 ± 0.33 m a −1 during the observation period. The highest thinning of − 1.69 ± 0.60 m a −1 was observed in the Pir Panjal while as the marginal thinning of − 0.11 ± 0.32 m a −1 was observed for the glaciers in the Karakoram. The observed glacier thickness changes indicated a strong influence of the topographic parameters. Higher thickness reduction was observed on the glaciers situated at lower altitudes (− 1.40 ± 0.53 m a −1 ) and with shallower slopes (− 1.52 ± 0.40 m a −1 ). Significantly higher negative thickness changes were observed from the glaciers situated on the southern slopes (− 0.55 ± 0.37 m a −1 ). The thickness loss was higher on the debris-covered glaciers (− 0.50 ± 0.38 m a −1 ) than on the clean glaciers (− 0.32 ± 0.33 m a −1 ). The cumulative glacier mass loss of − 70.32 ± 66.69 Gt was observed during the observation period, which, if continued, would significantly affect the sustainability of water resources in the basin.

Cataract caused by crystallin aggregation is the leading cause of vision impairment and blindness globally. The only available treatment option so far is surgery. In this study, we leverage lipid nanoparticles (LNPs)-formulated mRNA encoding human lanosterol synthase (hLSS) to elevate lanosterol levels in the lens as a potential anti-cataract therapy. hLSS mRNA delivered with aromatized LNPs can be avidly taken up and translated into hLSS proteins in mammalian cells. mRNA formulations administered via intravitreal, subconjunctival, intracameral, or subretinal injection in rats display distinct kinetics and bio-distribution profiles, among which intracameral injection achieves sustained and selective protein expression in the lens. In comparison to clinically used LNPs, aromatized LNPs show more than seven-fold higher mRNA delivery potency in rats upon intracameral injection, without inducing significant ocular lesions. Furthermore, ocular delivery of hLSS mRNA-loaded formulations leads to elevated levels of hLSS proteins and lanosterol within the lens and a remarkable improvement in cataract symptoms in two rat models of cataract. Collectively, topical delivery of hLSS mRNA-LNPs to the eyes offers a potential strategy to reduce intracellular aggregation of crystallins and ameliorate cataract development. Surgery is currently the only treatment option for cataract. Here, the authors report on ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase as a potential anti-cataract therapy, which ameliorates cataract development in two rat cataract models.

Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.

Main conclusionTwo key amino acids of isomultiflorenol synthase, Y125 and M254, were first proposed. They could be associated with the production of isomultiflorenol.Oxidosqualene cyclases (OSCs) are the first committed enzymes in the triterpenoid biosynthesis by converting 2,3-oxidosqualene to specific triterpenoid backbones. Thus, these enzymes are potential targets for developing plant-active compounds through the study of triterpenoid biosynthesis. We applied transcriptome information and metabolite profiling from Trichosanthes cucumerina L. to define the diversity of triterpenoids in this plant through OSCs. Isomultiflorenol synthase and cucurbitadienol synthase were previously identified in this plant. Here, three new OSCs, TcBAS, TcLAS, and TcCAS, were cloned and functionally characterized as β-amyrin synthase, lanosterol synthase, and cycloartenol synthase activities, respectively. We also took advantage of the multiple sequence alignment and molecular docking of OSCs exhibiting in this plant and other plant OSCs to identify key residues associated with isomultiflorenol synthase specificity. Two novel key amino acids, referred to the Y125 and M254, were first discovered. These results provide information on a possible catalytic mechanism for plant OSCs that produce specific products.

Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain tumor for which novel therapeutic approaches are desperately needed. Previous studies have shown that the menin inhibitor MI-2 exhibits promising activity in preclinical DIPG and adult glioma models, although the mechanism underlying this activity is unknown. Here, using an integrated approach, we show that MI-2 exerts its antitumor activity in glioma largely independent of its ability to target menin. Instead, we demonstrate that MI-2 activity in glioma is mediated by disruption of cholesterol homeostasis, with suppression of cholesterol synthesis and generation of the endogenous liver X receptor ligand, 24,25-epoxycholesterol, resulting in cholesterol depletion and cell death. Notably, this mechanism is responsible for MI-2 activity in both DIPG and adult glioma cells. Metabolomic and biochemical analyses identify lanosterol synthase as the direct molecular target of MI-2, revealing this metabolic enzyme as a vulnerability in glioma and further implicating cholesterol homeostasis as an attractive pathway to target in this malignancy.

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase ( LSS ), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights. Some cholesterol-lowering drugs can increase the risk of type 2 diabetes, but the mechanism behind this is not fully understood. Here the authors show that there is a single genetic regulatory module that influences both cholesterol levels and glucose levels, providing a link between cholesterol levels and diabetes.

The plant sterol pathway exhibits a major biosynthetic difference as compared with that of metazoans. The committed sterol precursor is the pentacyclic cycloartenol (9β,19-cyclolanost-24-en-3β-ol) and not lanosterol (lanosta-8,24-dien-3β-ol), as it was shown in the late sixties. However, plant genome mining over the last years revealed the general presence of lanosterol synthases encoding sequences (LAS1) in the oxidosqualene cyclase repertoire, in addition to cycloartenol synthases (CAS1) and to non-steroidal triterpene synthases that contribute to the metabolic diversity of C30H50O compounds on earth. Furthermore, plant LAS1 proteins have been unambiguously identified by peptidic signatures and by their capacity to complement the yeast lanosterol synthase deficiency. A dual pathway for the synthesis of sterols through lanosterol and cycloartenol was reported in the model Arabidopsis thaliana, though the contribution of a lanosterol pathway to the production of 24-alkyl-Δ(5)-sterols was quite marginal (Ohyama et al. (2009) PNAS 106, 725). To investigate further the physiological relevance of CAS1 and LAS1 genes in plants, we have silenced their expression in Nicotiana benthamiana. We used virus induced gene silencing (VIGS) based on gene specific sequences from a Nicotiana tabacum CAS1 or derived from the solgenomics initiative (http://solgenomics.net/) to challenge the respective roles of CAS1 and LAS1. In this report, we show a CAS1-specific functional sterol pathway in engineered yeast, and a strict dependence on CAS1 of tobacco sterol biosynthesis.