The origin of the statins

This study explored the impact of elicitors (sodium alginate (SA), microbial contamination in the form of Bacillus cereus (MC), and cholesterol) on the synthesis of lovastatin, (+)-geodin, and sulochrin by A. terreus during a 9-day period. Lovastatin production significantly increased with SA (200 mg/50 mL) and MC by approximately 5-fold at the end of fermentation, with significant increments observed as soon as day 3. In contrast, (+)-geodin production decreased (SA by 454% and MC by 138%), and sulochrin's pattern showed no clear concentration dependence. Gelatine, used as a viscosity control for SA, reduced all metabolites but improved biomass, indicating viscosity's negative impact on production. Cholesterol significantly increased lovastatin (18.68 mg/L, a 77.31% increase), though lower than SA and MC, and induced ∼2.6-fold higher (+)-geodin and sulochrin on day 9 at 200 mg/50 mL. In general, sulochrin levels were significantly higher with all elicitors, except for gelatine, on day 9. All elicitors induced changes in metabolite production compared to negative control, but their mechanisms differed. SA and MC primarily influenced lovastatin, showing rapid production as early as day 3. In contrast, cholesterol enhanced A. terreus morphology (small, compact and hairy), leading to an increase in metabolite production, although to a lesser extent than SA and MC.

Large-scale culture is a complementary and practical method for genome mining and OSMAC approaches to discover novel natural products through accumulation and reprocessing effects. By employing a large-scale culture approach, twelve 3,5-dimethylorsellinic acid (DMOA)-based meroterpenoids, including five undescribed compounds, namely asperanstinoids A–E, were obtained from fungus Aspergillus calidoustus, which was isolated from the wetland soil collected at Dianchi Lake, Yunnan Province. The structures and absolute configurations of asperanstinoids A–E were determined by various spectroscopic analyses, including NMR spectroscopy, high-resolution electrospray ionization mass spectrometry (HRESIMS), single-crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations, and the absolute configurations of three known compounds, dehydroaustinol, austinol, and austin, were confirmed via single-crystal X-ray diffraction for the first time. Notably, asperanstinoid A represents the second example of a DMOA-based meroterpenoid featuring a unique 6/5/6/6/6/5-fused hexacyclic skeleton with a rare “1,13-epoxy” moiety. The cytotoxicity assay of all these isolates revealed that asperanstinoid D, dehydroaustinol, and austin displayed considerable cytotoxicity against the HL-60 and SU-DHL-4 tumor cell lines with IC₅₀ values ranging from 15.7 to 27.8 μM.

Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin–kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)–lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C–induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients.

The term nutraceutical is derived from a combination of the words “nutrient” and “pharmaceutical” and, as it implies, refers to compounds derived from food sources and other types of intake that have particular beneficial health effects, other than their nutritional value. In recent years, a large number of studies have focused on an enormous quantity of such compounds, evaluating them for toxicological safety and potential benefits in situations as diverse as neurodegenerative disorders, obesity and diabetes, improvement of transplant success, and the fight against cancer. Mitochondria are a benchmark model for toxicity evaluation and the effects of nutraceuticals on mitochondrial activity are a quick and efficient protocol for toxicity and effects evaluation. We thus focus on commonly studied nutraceutical molecules and discuss to some extent the research performed on the various applications they might possess on a clinical setting, in particular focusing on known mitochondrial effects.

Aspergillus burnettii is a new species belonging to the A. alliaceus clade in Aspergillus subgenus Circumdati section Flavi isolated from peanut-growing properties in southern Queensland, Australia. A. burnettii is a fast-growing, floccose fungus with distinctive brown conidia and is a talented producer of biomass-degrading enzymes and secondary metabolites. Chemical profiling of A. burnettii revealed the metabolites ochratoxin A, kotanins, isokotanins, asperlicin E, anominine and paspalinine, which are common to subgenus Circumdati, together with burnettiene A, burnettramic acids, burnettides, and high levels of 14α-hydroxypaspalinine and hirsutide. The genome of A. burnettii was sequenced and an annotated draft genome is presented. A. burnettii is rich in secondary metabolite biosynthetic gene clusters, containing 51 polyketide synthases, 28 non-ribosomal peptide synthetases and 19 genes related to terpene biosynthesis. Functional annotation of digestive enzymes of A. burnettii and A. alliaceus revealed overlapping carbon utilisation profiles, consistent with a close phylogenetic relationship.

HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in the cholesterol biosynthetic pathway, and its catalytic domain is the well-known target of cholesterol-lowering drugs, statins. HMGCR is subject to layers of negative feedback loops; excess cholesterol inhibits transcription of the gene, and lanosterols and oxysterols accelerate degradation of HMGCR. A class of synthetic small molecules, bisphosphonate esters exemplified by SR12813, has been known to induce accelerated degradation of HMGCR and reduce the serum cholesterol level. Although genetic and biochemical studies revealed that the accelerated degradation requires the membrane domain of HMGCR and Insig, an oxysterol sensor on the endoplasmic reticulum membrane, the direct target of the bisphosphonate esters remains unclear. In this study, we developed a potent photoaffinity probe of the bisphosphonate esters through preliminary structure–activity relationship study and demonstrated binding of the bisphosphonate esters to the HMGCR membrane domain. These results provide an important clue to understand the elusive mechanism of the SR12813-mediated HMGCR degradation and serve as a basis to develop more potent HMGCR degraders that target the non-catalytic, membrane domain of the enzyme.