Search Results (18)

Non-alcoholic fatty liver disease (NAFLD) is among the most prevalent liver disorders globally, affecting approximately 25% to 40% of the adult population. Closely associated with metabolic syndrome, obesity, insulin resistance, and dyslipidemia, NAFLD presents a growing burden due to its increasing incidence and high healthcare costs. In this context, the development of effective preventive and therapeutic strategies remains a pressing challenge in modern medicine. This review aims to analyze current scientific evidence on bioactive plant compounds—particularly polyphenols and polyprenols—including their natural sources, mechanisms of action, and potential applications in the prevention and dietary management of NAFLD. A growing body of evidence demonstrates that both polyphenols and polyprenols exert hepatoprotective, antioxidant, anti-inflammatory, and hypolipidemic effects. These compounds modulate signaling pathways implicated in hepatic steatosis and fibrosis, positively influence gut microbiota composition, and affect bile acid metabolism. Studies have confirmed the efficacy of polyphenol-rich foods (naringenin, resveratrol, chlorogenic acid, etc.) and polyprenol-based formulations in reducing body weight and liver steatosis, improving biochemical markers and insulin resistance. The combined application of polyphenols and polyprenols may yield synergistic effects on multiple pathogenic pathways and represents a promising direction for the dietary prevention and management of NAFLD. Full article

Dolichols are isoprenoid end-products of the mevalonate and 2C-methyl-D-erythritol-4-phosphate pathways. The synthesis of dolichols is initiated with the addition of several molecules of isopentenyl diphosphate to farnesyl diphosphate. This reaction is catalyzed by a cis-prenyltransferase and leads to the formation of polyprenyl diphosphate. Subsequent steps involve the dephosphorylation and reduction of the α-isoprene unit by a polyprenol reductase, resulting in the generation of dolichol. The size of the dolichol varies, depending on the number of isoprene units incorporated. In eukaryotes, dolichols are synthesized as a mixture of four or more different lengths. Their biosynthesis is predicted to occur in the endoplasmic reticulum, where dolichols play an essential role in protein glycosylation. In this study, we have developed a selection of aptamers targeting dolichols and enhanced their specificity by incorporating fatty acids for negative selection. One aptamer showed high enrichment and specificity for linear polyisoprenoids containing at least one oxygen atom, such as an alcohol or aldehyde, in the α-isoprene unit. The selected aptamer proved to be a valuable tool for the subcellular localization of polyisoprenoids in the malaria parasite. To the best of our knowledge, this is the first time that polyisoprenoids have been localized within a cell using aptamer-based imaging techniques. Full article

The biosynthesis of subunits of rhizobial exopolysaccharides is dependent on glycosyltransferases, which are usually encoded by large gene clusters. PssA is a member of a large family of phosphoglycosyl transferases catalyzing the transfer of a phosphosugar moiety to polyprenol phosphate; thus, it can be considered as priming glycosyltransferase commencing synthesis of the EPS repeating units in Rhizobium leguminosarum. The comprehensive analysis of PssA protein features performed in this work confirmed its specificity for UDP-glucose and provided evidence that PssA is a monotopic inner membrane protein with a reentrant membrane helix rather than a transmembrane segment. The bacterial two-hybrid system screening revealed interactions of PssA with some GTs involved in the EPS octasaccharide synthesis. The distribution of differentially expressed genes in the transcriptome of the ΔpssA mutant into various functional categories indicated complexity of cell response to the deletion, which can mostly be attributed to the lack of exopolysaccharide and downstream effects caused by such deficiency. The block in the EPS biosynthesis at the pssA step, potentially leading to an increased pool of UDP-glucose, is likely to be filtered through to other pathways, and thus the absence of EPS may indirectly affect the expression of proteins involved in these pathways. Full article

Isoprenoids are the output of the polymerization of five-carbon, branched isoprenic chains derived from isopentenyl pyrophosphate (IPP) and its isomer, dimethylallyl pyrophosphate (DMAPP). Isoprene units are consecutively condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively), necessary for the biosynthesis of several metabolites. Polyprenyl transferases and synthases use polyprenyl pyrophosphates as their natural substrates; however, it is known that free polyprenols, such as farnesol (FOH), and geranylgeraniol (GGOH) can be incorporated into prenylated proteins, ubiquinone, cholesterol, and dolichols. Furthermore, FOH and GGOH have been shown to block the effects of isoprenoid biosynthesis inhibitors such as fosmidomycin, bisphosphonates, or statins in several organisms. This phenomenon is the consequence of a short pathway, which was observed for the first time more than 25 years ago: the polyprenol salvage pathway, which works via the phosphorylation of FOH and GGOH. Biochemical studies in bacteria, animals, and plants suggest that this pathway can be carried out by two enzymes: a polyprenol kinase and a polyprenyl-phosphate kinase. However, to date, only a few genes have been unequivocally identified to encode these enzymes in photosynthetic organisms. Nevertheless, pieces of evidence for the importance of this pathway abound in studies related to infectious diseases, cancer, dyslipidemias, and nutrition, and to the mitigation of the secondary effects of several drugs. Furthermore, nowadays it is known that both FOH and GGOH can be incorporated via dietary sources that produce various biological effects. This review presents, in a simplified but comprehensive manner, the most important data on the FOH and GGOH salvage pathway, stressing its biomedical importance The main objective of this review is to bring to light the need to discover and characterize the kinases associated with the isoprenoid salvage pathway in animals and pathogens. Full article

Protein glycosylation requires dolichyl phosphate as a carbohydrate carrier. Dolichols are α-saturated polyprenols, and their saturation in S. cerevisiae is catalyzed by polyprenyl reductase Dfg10 together with some other unknown enzymes. The aim of this study was to identify such enzymes in Candida. The Dfg10 polyprenyl reductase from S. cerevisiae comprises a C-terminal 3-oxo-5-alpha-steroid 4-dehydrogenase domain. Alignment analysis revealed such a domain in two ORFs (orf19.209 and orf19.3293) from C. albicans, which were similar, respectively, to Dfg10 polyprenyl reductase and Tsc13 enoyl-transferase from S. cerevisiae. Deletion of orf19.209 in Candida impaired saturation of polyprenols. The Tsc13 homologue turned out not to be capable of saturating polyprenols, but limiting its expression reduce the cellular level of dolichols and polyprenols. This reduction was not due to a decreased expression of genes encoding cis-prenyltransferases from the dolichol branch but to a lower expression of genes encoding enzymes of the early stages of the mevalonate pathway. Despite the resulting lower consumption of acetyl-CoA, the sole precursor of the mevalonate pathway, it was not redirected towards fatty acid synthesis or elongation. Lowering the expression of TSC13 decreased the expression of the ACC1 gene encoding acetyl-CoA carboxylase, the key regulatory enzyme of fatty acid synthesis and elongation. Full article

Exopolysaccharides (EPS) play critical roles in rhizobium-plant interactions. However, the EPS biosynthesis pathway in Bradyrhizobium diazoefficiens USDA110 remains elusive. Here we used transposon (Tn) mutagenesis with the aim to identify genetic elements required for EPS biosynthesis in B. diazoefficiens USDA110. Phenotypic screening of Tn5 insertion mutants grown on agar plates led to the identification of a mutant with a transposon insertion site in the blr2358 gene. This gene is predicted to encode a phosphor-glycosyltransferase that transfers a phosphosugar onto a polyprenol phosphate substrate. The disruption of the blr2358 gene resulted in defective EPS synthesis. Accordingly, the blr2358 mutant showed a reduced capacity to induce nodules and stimulate the growth of soybean plants. Glycosyltransferase genes related to blr2358 were found to be well conserved and widely distributed among strains of the Bradyrhizobium genus. In conclusion, our study resulted in identification of a gene involved in EPS biosynthesis and highlights the importance of EPS in the symbiotic interaction between USDA110 and soybeans. Full article

Sixteen strains of five genera of thermophilic bacteria, i.e., Alicyclobacillus, Brevibacillus, Geobacillus, Meiothermus, and Thermus, were cultivated at a temperature from 42 to 70 °C. Twelve strains were obtained from the Czech Collection of Microorganisms, while four were directly isolated and identified by 16S rRNA gene sequencing from the hot springs of the world-famous Carlsbad spa (Czech Republic). Polyprenol homologs from C40 to C65 as well as free undecaprenol (C55), undecaprenyl phosphate, and undecaprenyl diphosphate were identified by shotgun analysis and RP-HPLC/MS-ESI⁺ (reverse phase high-performance liquid chromatography–high-resolution positive electrospray ionization mass spectrometry). The limit of detection (50 pM) was determined for individual homologs and free polyprenols and their phosphates. Thus, it has been shown that at least some thermophilic bacteria produce not just the major C55 polyprenol as previously described, but a mixture of homologs. Full article

The needles of conifer trees are one of the richest sources of natural polyprenols. Polyprenol homologs from Abies sibirica L. lipophilic 80% purified extract were analyzed and quantified. In total, 10 peaks (Prenol-11 to Prenol-20) were observed in the ultra-high-performance liquid chromatography–diode array detector (UHPLC-DAD) chromatogram of Siberian fir with the most abundant compound being Prenol-15 (relative amount 37.23 + 0.56% of the total polyprenol yield). Abies sibirica L. polyprenol solubility and incorporation efficiency into liposomes were studied in various commercially available lecithin mixtures (Phosal IP40, Phosal 75SA, and Lipoid P45). The resulting multilamellar polyprenol liposomes were morphologically characterized by Light and Transmission Electron Microscopy, and the liposome size was discovered to be polymodal with the main peak at 1360 nm (90% of the volume). As polyprenols are fully soluble only in lipids, a liposomal formulation based upon co-solubilization and a modified ethanol injection method of polyprenols into the ethanol-phospholipid system was developed for the entrapment and delivery of polyprenols for potential commercial applications in food supplement and cosmetic industries. Full article

Membrane regulators such as sterols and hopanoids play a major role in the physiological and physicochemical adaptation of the different plasmic membranes in Eukarya and Bacteria. They are key to the functionalization and the spatialization of the membrane, and therefore indispensable for the cell cycle. No archaeon has been found to be able to synthesize sterols or hopanoids to date. They also lack homologs of the genes responsible for the synthesis of these membrane regulators. Due to their divergent membrane lipid composition, the question whether archaea require membrane regulators, and if so, what is their nature, remains open. In this review, we review evidence for the existence of membrane regulators in Archaea, and propose tentative location and biological functions. It is likely that no membrane regulator is shared by all archaea, but that they may use different polyterpenes, such as carotenoids, polyprenols, quinones and apolar polyisoprenoids, in response to specific stressors or physiological needs. Full article

Arabidopsis roots accumulate a complex mixture of dolichols composed of three families, (i.e., short-, medium- and long-chain dolichols), but until now none of the cis-prenyltransferases (CPTs) predicted in the Arabidopsis genome has been considered responsible for their synthesis. In this report, using homo- and heterologous (yeast and tobacco) models, we have characterized the AtCPT1 gene (At2g23410) which encodes a CPT responsible for the formation of long-chain dolichols, Dol-18 to -23, with Dol-21 dominating, in Arabidopsis. The content of these dolichols was significantly reduced in AtCPT1 T-DNA insertion mutant lines and highly increased in AtCPT1-overexpressing plants. Similar to the majority of eukaryotic CPTs, AtCPT1 is localized to the endoplasmic reticulum (ER). Functional complementation tests using yeast rer2Δ or srt1Δ mutants devoid of medium- or long-chain dolichols, respectively, confirmed that this enzyme synthesizes long-chain dolichols, although the dolichol chains thus formed are somewhat shorter than those synthesized in planta. Moreover, AtCPT1 acts as a homomeric CPT and does not need LEW1 for its activity. AtCPT1 is the first plant CPT producing long-chain polyisoprenoids that does not form a complex with the NgBR/NUS1 homologue. Full article

In the yeast Saccharomyces cerevisiae, components of the High Osmolarity Glycerol (HOG) pathway are important for the response to diverse stresses including response to endoplasmic reticulum stress (ER stress), which is produced by the accumulation of unfolded proteins in the lumen of this organelle. Accumulation of unfolded proteins may be due to the inhibition of protein N-glycosylation, which can be achieved by treatment with the antibiotic tunicamycin (Tn). In this work we were interested in finding proteins involved in the ER stress response regulated by Hog1, the mitogen activated protein kinase (MAPK) of the HOG pathway. A high gene dosage suppression screening allowed us to identify genes that suppressed the sensitivity to Tn shown by a hog1Δ mutant. The suppressors participate in a limited number of cellular processes, including lipid/carbohydrate biosynthesis and protein glycosylation, vesicle-mediated transport and exocytosis, cell wall organization and biogenesis, and cell detoxification processes. The finding of suppressors Rer2 and Srt1, which participate in the dolichol biosynthesis pathway revealed that the hog1Δ strain has a defective polyprenol metabolism. This work uncovers new genetic and functional interactors of Hog1 and contributes to a better understanding of the participation of this MAPK in the ER stress response. Full article

Three polyisoprenoid alcohols were isolated from the leaves of Tournefortia hirsutissima by a bioassay-guided phytochemical investigation. The compounds were identified as 16-hydroxy-lycopersene (Compound 1), (Z₈,E₃,ω)-dodecaprenol (Compound 2) and (Z₉,E₃,ω)-tridecaprenol (Compound 3). Compound 1, an unusual polyisoprenoid, was characterized by 1D and 2D NMR. We also determined the absolute configuration at C-16 by the modified Mosher’s method. The in vitro antiproliferative and anti-inflammatory activities of the isolated compounds were evaluated. Among isolates, Compound 1 moderately inhibited the nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. On the other hand, Compound 1 displayed selective antiproliferative activity against HeLa, PC3, HepG2 and Hep3B cancer cells and was less potent against IHH non-cancerous cells. Compound 1 in Hep3B cells showed significant inhibition of cell cycle progression increasing the sub-G₁ phase, suggesting cell death. Acridine orange/ethidium bromide staining and Annexin V-FITC/PI staining demonstrated that cell death induced by Compound 1 in cells Hep3B was by apoptosis. Further study showed that apoptosis induced by Compound 1 in Hep3b cells is associated with the increase of the ratio of Bax/Bcl-2, and caspase 3/7 activation. These results suggest that Compound 1 induce apoptotic cell death by the mitochondrial pathway. To our knowledge, this is the first report about the presence of polyprenol Compounds 1–3 in T. hirsutissima, and the apoptotic and anti-inflammatory action of Compound 1. Full article

Mono-saturated polyprenols (dolichols) have been found in almost all Eukaryotic cells, however, dolichols containing additional saturated bonds at the ω-end, have been identified in A. fumigatus and A. niger. Here we confirm using an LC-ESI-QTOF-MS analysis, that poly-saturated dolichols are abundant in other filamentous fungi, Trichoderma reesei, A. nidulans and Neurospora crassa, while the yeast Saccharomyces cerevisiae only contains the typical mono-saturated dolichols. We also show, using differential scanning calorimetry (DSC) and fluorescence anisotropy of 1,6-diphenyl-l,3,5-hexatriene (DPH) that the structure of dolichols modulates the properties of membranes and affects the functioning of dolichyl diphosphate mannose synthase (DPMS). The activity of this enzyme from T. reesei and S. cerevisiae was strongly affected by the structure of dolichols. Additionally, the structure of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) model membranes was more strongly disturbed by the poly-saturated dolichols from Trichoderma than by the mono-saturated dolichols from yeast. By comparing the lipidome of filamentous fungi with that from S. cerevisiae, we revealed significant differences in the PC/PE ratio and fatty acids composition. Filamentous fungi differ from S. cerevisiae in the lipid composition of their membranes and the structure of dolichols. The structure of dolichols profoundly affects the functioning of dolichol-dependent enzyme, DPMS. Full article

Background and objective: Statin-induced myopathy (SIM) has been partially attributed to deficiency of dolichol and coenzyme Q10 (CoQ10). We aimed to test the safety and efficacy of plant polyprenols in combination with CoQ10 for alleviation of SIM.
Materials and methods: In an open-label, one-center prospective pilot study patients with SIM received conifer-tree needle polyprenols (4 mg/day) and CoQ10 (100 mg/day) for 8 weeks. Symptoms and safety were evaluated according to symptom severity score (0–10), creatine kinase (CK) levels, exercise test, dynamometry, complete blood count, clinical biochemistry and electrocardiography.
Results: Of the 14 patients, 11 completed the study per protocol. Two patients withdrew consent due to travels abroad, and it was discontinued for one patient with stage 3 chronic kidney disease due to asymptomatic elevations of liver enzymes at week 4. No safety parameters changed significantly in per protocol group. Non-significant increase of CK levels was observed (P = 0.231). Muscle pain (n = 10) and weakness (n = 7) scores improved significantly (P < 0.001 and P = 0.018, respectively). Muscle pain completely disappeared in 2 patients, weakness resolved in 3 patients and cramps disappeared in two patients. Four patients assessed improvement strong enough to consider increase of statin dose. No changes were observed in exercise test or dynamometry.
Conclusions: Conifer-tree polyprenols in combination with CoQ10 may be generally safe in patients with SIM, but caution should be exercised in patients with glomerular filtration rate <60 mL/min and routine monitoring of the liver enzymes and CK is advocated in all patients. The observed efficacy provides the rationale for a larger, double-blind controlled study with polyprenols. Full article

In this study, high performance liquid chromatography (HPLC), ultraviolet (UV), thermagravimetric analyzer (TGA), pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS), and scanning electron microscope (SEM) were used as measurement techniques, contents of chemical composition, pyrolytic products, thermal stability, morphological characterization of Ginkgo biloba leaves (GBL) acted as the index, and physicochemical properties of GBL after enzymolysis based ultrasound extraction (EBUE) and Soxhlet extraction were studied. The detection results of chemical composition revealed that contents of general flavone, soluble protein, soluble total sugar and protein in the GBL declined significantly after EBUE, and contents of polyprenols and crude fat obviously reduced as well after Soxhlet extraction. Py-GC-MS results indicated that total GC contents of micromolecules with carbon less than 12 from 54.0% before EBUE decline to 8.34% after EBUE. Total GC contents of long-chain fatty acids with carbon less than 20 from 43.0% before EBUE reduced to 27.0% after Soxhlet extraction. Thermal stability results showed that GBL after Soxhlet extraction was easier to decompose than GBL before EBUE. SEM results illustrated that surface structure of GBL was damaged severely after EBUE, compared with GBL before EBUE, while organic solvent extraction had little influence on the morphological characterization of GBL after Soxhlet extraction compared with GBL after EBUE. Full article