Inhibition Of Fatty Acid Synthesis Research Articles

Regulation of Rice Grain Weight by Fatty Acid Composition: Unveiling the Mechanistic Roles of OsLIN6 by OsARF12.

Fatty acids play a putative role as second messengers of phytohormones and regulate the rice grain weight. However, the inner mechanism is still unclear and needs to be further studied. In this study, we identified that oleic acid (C18:1) negatively correlates while linoleic acid (C18:2) positively correlates with rice grain weight. Field trials showed that 1000-grain weight was significantly reduced when treated with the fatty acid synthesis inhibitor, Firsocostat S enantiomer (FSE), at the heading and flowering stages. RNA-seq analysis revealed that FSE affects grain weight by modulating processes, such as glycolysis, sucrose metabolism, and hormone signaling. Notably, FSE inhibited the expression of OsLIN6, which is responsible for transporting C18:1 to the phosphatidylcholine pool for C18:2 synthesis. Compared with the wild type (WT), the OsLIN6 knockout mutant exhibited a lower grain weight, an increased C18:1 content, and a decreased C18:2 content. Importantly, OsARF12 was shown to bind to the OsLIN6 promoter and activate its expression. In summary, this study highlights the crucial role of the fatty acid synthesis gene, OsLIN6, which was regulated by OsARF12, in rice grain weight determination, thus establishing the molecular link between fatty acid synthesis and auxin signaling.

Phosphorylation of Insig-2 mediates inhibition of fatty acid synthesis by polyunsaturated fatty acids

Insig-1 and Insig-2 are endoplasmic reticulum (ER) proteins that inhibit lipid synthesis by blocking transport of sterol regulatory element-binding proteins (SREBP-1 and SREBP-2) from ER to Golgi. In the Golgi, SREBPs are processed proteolytically to release their transcription-activating domains, which enhance the synthesis of fatty acids, triglycerides, and cholesterol. Heretofore, the two Insigs have redundant functions, and there is no rationale for two isoforms. The current data identify a specific function for Insig-2. We show that eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, inhibits fatty acid synthesis in human fibroblasts and rat hepatocytes by activating adenylate cyclase, which induces protein kinase A (PKA) to phosphorylate serine-106 in Insig-2. Phosphorylated Insig-2 inhibits the proteolytic processing of SREBP-1, thereby blocking fatty acid synthesis. Phosphorylated Insig-2 does not block the processing of SREBP-2, which activates cholesterol synthesis. Insig-1 lacks serine-106 and is not phosphorylated at this site. EPA inhibition of SREBP-1 processing was reduced by the replacement of serine-106 in Insig-2 with alanine or by treatment with KT5720, a PKA inhibitor. Inhibition did not occur in mutant human fibroblasts that possess Insig-1 but lack Insig-2. These data provide an Insig-2-specific mechanism for the long-known inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Hepatoprotective effects and mechanisms of l-theanine and epigallocatechin gallate combined intervention in alcoholic fatty liver rats.

Chronic excessive alcohol consumption can lead to alcoholic fatty liver, posing substantial health risks. l-Theanine (LTA) and epigallocatechin gallate (EGCG) in tea exert antioxidant and hepatoprotective effects. However, the combined effects of LTA and EGCG on rats with alcoholic fatty liver, and the underlying mechanisms of such effects, remain unclear. In this study, Sprague Dawley (SD) rats were fed with alcohol for 6 weeks to induce alcoholic fatty liver. Subsequently, for another 6 weeks, the rats were administered LTA (200 mg kg-1 day-1), EGCG (200 mg kg-1 day-1), or a combination of LTA with EGCG (40 mg kg-1 day-1 l-Thea +160 mg kg-1 day-1 EGCG), respectively. The combined use of LTA and EGCG for alcoholic fatty liver disease had more significant effects than their individual administration. This combination reduced the activity of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as the levels of hepatic triglyceride (TG), malondialdehyde (MDA), and reactive oxygen species (ROS) in the rats. The combined intervention also increased hepatic superoxide dismutase (SOD) and glutathione peroxidase activity. Reductions in hepatic fat accumulation and inflammatory responses were observed. The mechanism underlying these effects primarily involved the inhibition of fatty acid synthesis and the alleviation of lipid peroxidation through the downregulation of the mRNA and protein expression of TNF-α, SREBP1c, and CYP2E1 and the upregulation of the mRNA and protein expression of ADH1, ALDH2, Lipin-1, PPARαPPARα, AMPK, and PGC-1α, thereby promoting the oxidative decomposition of fatty acids and reducing the synthesis of cholesterol and glucose. l-Theanine and EGCG appear to be able to alleviate alcoholic fatty liver by modulating lipid metabolism and ameliorating oxidative stress, indicating their potential as natural active ingredients in anti-alcoholic fatty liver food products. © 2024 Society of Chemical Industry.

Nitrogen availability is important for preventing catastrophic mitosis in fission yeast.

Mitosis is a crucial stage in the cell cycle, controlled by a vast network of regulators responding to multiple internal and external factors. The fission yeast Schizosaccharomyces pombe demonstrates catastrophic mitotic phenotypes due to mutations or drug treatments. One of the factors provoking catastrophic mitosis is a disturbed lipid metabolism, resulting from, for example, mutations in the acetyl-CoA/biotin carboxylase (cut6), fatty acid synthase (fas2, also known as lsd1) or transcriptional regulator of lipid metabolism (cbf11) genes, as well as treatment with inhibitors of fatty acid synthesis. It has been previously shown that mitotic fidelity in lipid metabolism mutants can be partially rescued by ammonium chloride supplementation. In this study, we demonstrate that mitotic fidelity can be improved by multiple nitrogen sources. Moreover, this improvement is not limited to lipid metabolism disturbances but also applies to a number of unrelated mitotic mutants. Interestingly, the partial rescue is not achieved by restoring the lipid metabolism state, but rather indirectly. Our results highlight a novel role for nitrogen availability in mitotic fidelity.

Genome-wide study of glutathione transferases and their regulation in flufenacet susceptible and resistant black-grass (Alopecurus myosuroides Huds.).

Glutathione transferases (GSTs) are enzymes with a wide range of functions, including herbicide detoxification. Up-regulation of GSTs and their detoxification activity enables the grass weed black-grass (Alopecurus myosuroides Huds.) to metabolize the very-long-chain fatty acid synthesis inhibitor flufenacet and other herbicides leading to multiple herbicide resistance. However, the genomic organization and regulation of GSTs genes is still poorly understood. In this genome-wide study the location and expression of 115 GSTs were investigated using a recently published black-grass genome. Particularly, the most abundant GSTs of class tau and phi were typically clustered and often followed similar expression patterns but possessed divergent upstream regulatory regions. Similarities were found in the promoters of the most up-regulated GSTs, which are located next to each other in a cluster. The binding motif of the E2F/DP transcription factor complex in the promoter of an up-regulated GST was identical in susceptible and resistant plants, however, adjacent sequences differed. This led to a stronger binding of proteins to the motif of the susceptible plant, indicating repressor activity. This study constitutes the first analysis dealing with the genomic investigation of GST genes found in black-grass and their transcriptional regulation. It highlights the complexity of the evolution of GSTs in black-grass, their duplication and divergence over time. The large number of GSTs allows weeds to detoxify a broad spectrum of herbicides. Ultimately, more research is needed to fully elucidate the regulatory mechanisms of GST expression. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Fish oil consumption prevents hepatic lipid accumulation induced by high-cholesterol feeding in obese KK mice.

Fish oil (FO) is rich in the n-3 polyunsaturated fatty acids. It has been demonstrated that FO intake possesses lipid-lowering properties. Conversely, a high-cholesterol (CH) diet promotes lipid accumulation in the liver and induces fatty liver. This study investigated the effects of FO feeding on hepatic lipid accumulation induced by high-cholesterol feeding in KK mice. All experimental diets had a fat energy ratio of 25%, the SO group had all fat sources as safflower oil (SO), the 12.5 FO group had half of the SO replaced with FO, and the 25 FO group had all of the SO replaced with FO, each with or without 2 weight % (wt%) cholesterol (SO/CH, 12.5 FO/CH, and 25 FO/CH groups, respectively), for 8 weeks. The hepatic triglyceride and total cholesterol levels were significantly lower in the 25 FO/CH group than in the SO/CH group. The hepatic mRNAs of fatty acid synthesis-related genes were downregulated by the FO feeding groups. In view of importance to establish the benefit of FO for preventing severe NAFLD, our results suggest that FO intake prevents excessive hepatic fat accumulation induced by a high-cholesterol diet in obese KK mice through the inhibition of fatty acid synthesis.

TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis

BackgroundTandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood.MethodsTumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays.ResultsHere, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level.ConclusionsAltogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Elucidating the impact of bacterial lipases, human serum albumin, and FASII inhibition on the utilization of exogenous fatty acids by Staphylococcus aureus.

Incorporation of host-derived exogenous fatty acids (eFAs), particularly unsaturated fatty acids (UFAs), by Staphylococcus aureus could affect the bacterial membrane fluidity and susceptibility to antimicrobials. In this work, we found that glycerol ester hydrolase (Geh) is the primary lipase hydrolyzing cholesteryl esters and, to a lesser extent, triglycerides and that human serum albumin (HSA) could serve as a buffer of eFAs, where low levels of HSA facilitate the utilization of eFAs but high levels of HSA inhibit it. The fact that the type II fatty acid synthesis (FASII) inhibitor, AFN-1252, leads to an increase in UFA content even in the absence of eFA suggests that membrane property modulation is part of its mechanism of action. Thus, Geh and/or the FASII system look to be promising targets to enhance S. aureus killing in a host environment by restricting eFA utilization or modulating membrane properties, respectively.

Redox-mediated activation of ATG3 promotes ATG8 lipidation and autophagy progression in Chlamydomonas reinhardtii.

Autophagy is one of the main degradative pathways used by eukaryotic organisms to eliminate useless or damaged intracellular material to maintain cellular homeostasis under stress conditions. Mounting evidence indicates a strong interplay between the generation of reactive oxygen species and the activation of autophagy. Although a tight redox regulation of autophagy has been shown in several organisms, including microalgae, the molecular mechanisms underlying this control remain poorly understood. In this study, we have performed an in-depth in vitro and in vivo redox characterization of ATG3, an E2-activating enzyme involved in ATG8 lipidation and autophagosome formation, from 2 evolutionary distant unicellular model organisms: the green microalga Chlamydomonas (Chlamydomonas reinhardtii) and the budding yeast Saccharomyces cerevisiae. Our results indicated that ATG3 activity from both organisms is subjected to redox regulation since these proteins require reducing equivalents to transfer ATG8 to the phospholipid phosphatidylethanolamine. We established the catalytic Cys of ATG3 as a redox target in algal and yeast proteins and showed that the oxidoreductase thioredoxin efficiently reduces ATG3. Moreover, in vivo studies revealed that the redox state of ATG3 from Chlamydomonas undergoes profound changes under autophagy-activating stress conditions, such as the absence of photoprotective carotenoids, the inhibition of fatty acid synthesis, or high light irradiance. Thus, our results indicate that the redox-mediated activation of ATG3 regulates ATG8 lipidation under oxidative stress conditions in this model microalga.

Transcriptomic and metabolomic characterization of antibacterial activity of Melastoma dodecandrum.

Antibacterial resistance poses a significant global threat, necessitating the discovery of new therapeutic agents. Plants are a valuable source of secondary metabolites with demonstrated anticancer and antibacterial properties. In this study, we reveal that Melastoma dodecandrum exhibits both bacteriostatic and bactericidal effects against Pseudomonas aeruginosa and Staphylococcus aureus. Treatment with plant extracts results in membrane damage and a reduction in P.aeruginosa swimming and swarming motility. A comparative analysis of bacterial transcriptomes exposed to M.dodecandrum extracts and four distinct antibiotics indicates that the extracts may trigger similar transcriptomic responses as triclosan, a fatty acid synthesis inhibitor. Activity-guided fractionation suggests that the antibacterial activity is not attributable to hydrolyzable tannins, but to unidentified minor compounds. Additionally, we identified 104 specialized metabolic pathways and demonstrated a high level of transcriptional coordination between these biosynthetic pathways and phytohormones, highlighting potential regulatory mechanisms of antibacterial metabolites in M.dodecandrum.

Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation.

Metabolic remodeling is one of the earliest events that occur during cell differentiation. Here, we define fatty acid metabolism as a key player in definitive endoderm differentiation from human embryonic stem cells. Fatty acid β-oxidation is enhanced while lipogenesis is decreased, and this is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase by AMPK. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist significantly promotes human endoderm differentiation, while blockade of fatty acid oxidation impairs differentiation. Mechanistically, reduced de novo fatty acid synthesis and enhanced fatty acid β-oxidation both contribute to the accumulation of intracellular acetyl-CoA, which guarantees the acetylation of SMAD3 and further causes nuclear localization to promote endoderm differentiation. Thus, our current study identifies a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role for fatty acid metabolism in regulating human endoderm differentiation.

Docosapentaenoic acid-rich oil lowers plasma glucose and lipids in a mouse model of diabetes and mild obesity

Many studies have investigated the beneficial effects of n-3 polyunsaturated fatty acids, such as their potential for lowering lipid levels and reducing diabetes risk. However, few studies have specifically examined docosapentaenoic acid (DPA), an n-3 polyunsaturated fatty acid with limited availability in its pure form. We hypothesized that DPA would have lipid-lowering effects and improve insulin resistance in KK/Ta mice. To test our hypothesis, 7-week-old KK/Ta mice were fed a high-fat diet for 12 weeks to induce obesity before being divided into 3 groups and fed an experimental diet for 10 weeks. The experimental diets were: LSO, using lard and safflower oil as fat sources; SO, in which lard in the LSO diet was replaced with safflower oil; and DPA, in which lard in the LSO diet was replaced with DPA oil. After 10 weeks, plasma triglyceride and total cholesterol concentrations were significantly decreased in the DPA group, but not in the SO group. Sterol regulatory element-binding protein-1 and stearoyl-CoA desaturase-1 gene expressions involved in fatty acid synthesis in the liver were significantly lower in the DPA group compared with the LSO group. Plasma glucose concentrations were significantly decreased in both the SO group and the DPA group compared with the LSO group, whereas plasma insulin concentrations were significantly decreased in the DPA group alone. These results indicate that DPA has plasma lipid-lowering and hypoglycemic effects, possibly from suppression of fatty acid synthesis in the liver.

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss. While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed. ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

Identification of a herbicide-resistant biotype of Echinochloa crus-galli in Ukraine

Ukraine is one of the world’s guarantors of food security and has the potential to further increase agricultural production. However, the vast majority of herbicides used on crops are acetolactate synthase (ALS) inhibitors, which poses a threat of herbicide-resistant weed species. The emergence and spread of herbicide-resistant weed biotypes can significantly increase the cost of growing crops to the point of loss of profitability. Herbicide resistance in barnyardgrass (Echinochloa crus-galli var. crus-galli) has been studied in long-term field and greenhouse experiments. Resistance of E. crus-galli to the ALS herbicide triazolopyrimidine derivative ‒ penoxsulam was identified. Expressed resistance was observed in weed plants grown from seeds collected under production conditions in Kherson region in 2015–2016 and 2020–2021. Cross resistance was observed for imidazolinone and sulfonylurea derivatives. It should be noted that the level of cross resistance to ALS herbicides was slightly higher for plants derived from weed seeds harvested in 2020–2021 compared to those harvested in 2015–2016. The introduction of a herbicidal composition of a herbicide mixture ‒ an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD) (an enzyme in plants in the chain of carotenoid synthesis) ‒ mesotrione with an ALS-inhibitor (nicosulfuron) allowed effective control of the weed, which indicates the absence of multiple resistance to herbicides ‒ inhibitors of carotenoid synthesis. The high efficiency of E. crus-galli control was established by the application of herbicides ‒ inhibitors of fatty acid synthesis (graminicides). The highest level of efficiency in the experiments was observed with the application of fluazifop-butyl and somewhat less ‒ with pinoxaden. A tendency to reduce phytotoxicity to barnyardgrass from the south of Ukraine was observed with the introduction of tepraloxydim and quizalofop-ethyl. A lower level of phytotoxicity of fenoxaprop-p-ethyl on E. crus-galli should be noted compared to the effect of pinoxaden. No multiple resistance was observed with glyphosate (5-enolpyruvylshikimate-3-phosphate synthase inhibitor) and reglone (photosystem I inhibitor), allowing control of vegetative weeds at the beginning and end of the growing season. It has been established that monocot weed species have significantly increased their presence and harmfulness in agrophytocenoses in Ukraine and in the world since the 1950s with the widespread introduction of selective dicotyledonous species control with aryloxyphenoxyacetic, propionic and benzoic acid derivatives. This trend has been maintained until recently ‒ barnyardgrass is one of the dominant weed species in modern agrophytocenoses of Ukraine. Therefore, the identification of the ALS-resistant biotype of barnyardgrass complicates weed control in the following crops in rotations in the southern regions of the country: in maize crops with cross resistance to nicosulfuron, in sunflower ‒ to imidazolinones (imazamox, imazapyr), and also makes it impossible to use penoxsulam in rice production. Traditionally, the use of synthetic auxins, phenoxyacetic acid derivatives, etc. is used to control ALS-resistance. However, in Kherson region of Ukraine, already in the third year of application of rinskor (florpyrauxifen-benzyl), some weed plants were found on rice fields affected by ALS-resistant barnyardgrass, which recovered after the use of synthetic auxin. Therefore, the control of ALS-resistance (penoxsulam, etc.) in E. crus-galli with the application florpyrauxifen-benzyl in the Kherson region of Ukraine is already limited. An obvious and economically feasible preventive measure against the emergence of resistant weed biotypes is the implementation of GAP (Good Agricultural Practice, FAO) approaches: in particular, the use of high quality seeds without weed impurities, increasing the proportion of agrotechnical weed control measures, restoring and expanding crop rotations with mandatory rotation of herbicides with different modes of action, introducing dicotyledonous/leguminous crops into rotations, and using herbicides with different modes of action in crops separately or in mixtures. At the same time, agrotechnical measures and the preservation of biodiversity in agrophytocenoses should be the main factor in controlling resistance in weeds. The use of herbicides and their mixtures with different modes of action is of secondary importance. The identification of highly damaging ALS-resistant E. crus-galli in southern Ukraine indicates the insufficient effectiveness of weed control exclusively with herbicides with a single mechanism of action and requires a significant revision of the principles of crop rotation and ways of weed control in the country to maintain high levels of profitability and productivity of agrophytocenoses. Solving this problem is urgent for the preservation of Ukraine's potential as one of the guarantors of global food security.

Gentamicin resistance to Escherichia coli related to fatty acid metabolism based on transcriptome analysis.

Antibiotic overuse and misuse have promoted the emergence and spread of antibiotic-resistant bacteria. Increasing bacterial resistance to antibiotics is a major healthcare problem, necessitating elucidation of antibiotic resistance mechanisms. In this study, we explored the mechanism of gentamicin resistance by comparing the transcriptomes of antibiotic-sensitive and -resistant Escherichia coli. A total of 410 differentially expressed genes were identified, of which 233 (56.83%) were up-regulated and 177 (43.17%) were down-regulated in the resistant strain compared with the sensitive strain. Gene Ontology (GO) analysis classifies differential gene expression into three main categories: biological processes, cellular components, and molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the up-regulated genes were enriched in eight metabolic pathways, including fatty acid metabolism, which suggests that fatty acid metabolism may be involved in the development of gentamicin resistance in E. coli. This was demonstrated by measuring the acetyl-CoA carboxylase activity, plays a fundamental role in fatty acid metabolism, was increased in gentamicin-resistant E. coli. Treatment of fatty acid synthesis inhibitor, triclosan, promoted gentamicin-mediated killing efficacy to antibiotic-resistant bacteria. We also found that exogenous addition of oleic acid, which involved in fatty acid metabolism, reduced E. coli sensitivity to gentamicin. Overall, our results provide insight into the molecular mechanism of gentamicin resistance development in E. coli.

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states

Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional ‘tissue-states’ defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.

Inhibiting fatty acid synthesis overcomes colistin resistance.

Treating multidrug-resistant infections has increasingly relied on last-resort antibiotics, including polymyxins, for example colistin. As polymyxins are given routinely, the prevalence of their resistance is on the rise and increases mortality rates of sepsis patients. The global dissemination of plasmid-borne colistin resistance, driven by the emergence of mcr-1, threatens to diminish the therapeutic utility of polymyxins from an already shrinking antibiotic arsenal. Restoring sensitivity to polymyxins using combination therapy with sensitizing drugs is a promising approach to reviving its clinical utility. Here we describe the ability of the biotin biosynthesis inhibitor, MAC13772, to synergize with colistin exclusively against colistin-resistant bacteria. MAC13772 indirectly disrupts fatty acid synthesis (FAS) and restores sensitivity to the last-resort antibiotic, colistin. Accordingly, we found that combinations of colistin and other FAS inhibitors, cerulenin, triclosan and Debio1452-NH3, had broad potential against both chromosomal and plasmid-mediated colistin resistance in chequerboard and lysis assays. Furthermore, combination therapy with colistin and the clinically relevant FabI inhibitor, Debio1452-NH3, showed efficacy against mcr-1 positive Klebsiella pneumoniae and colistin-resistant Escherichia coli systemic infections in mice. Using chemical genomics, lipidomics and transcriptomics, we explored the mechanism of the interaction. We propose that inhibiting FAS restores colistin sensitivity by depleting lipid synthesis, leading to changes in phospholipid composition. In all, this work reveals a surprising link between FAS and colistin resistance.

Evaluation of the interaction between ketone bodies and obesity-associated proteins: an in silico approach

Introduction: Obesity is an upsurge in body fat and is associated with a number of cardiovascular and metabolic conditions, including type-2 diabetes, atherosclerosis, dyslipidaemia, hypertension, and several malignancies. The ketogenic diet, which is high in fat and protein and very low in carbohydrates, has become one of the most researched options for weight loss in recent years. It has also recently gained recognition as a metabolic therapy for its efficacious methods in the prevention and treatment of cancer, type 2 diabetes, obesity, and other illnesses. Methods: This study was carried out to investigate the interaction of ketogenic diet end products, the ketone bodies (acetoacetate, acetone and beta-hydroxybutyrate) and standard drugs (orlistat and cetilistat) on selected obesity-related proteins including ghrelin, leptin, fat mass and obesity-associated (FTO) gene protein (PDB id: 3LFM), catalase, superoxide dismutase and 3-hydroxyl-3-methylgluatarate Co-A (HMG CoA) reductase in vivo. Results: In silico docking simulations of the proteins and ligands (standard drugs and ketone bodies) was done using high computing tools and software. The results revealed varied docking scores based on interactions between the proteins and ligands. The standard drugs and ketone bodies exhibited good docking scores for all the proteins docked, although the standard drugs had slightly higher scores in most cases except for FTO, for which the ketone bodies had higher docking scores. This implies that the FTO–ketone bodies complex might activate the inhibition of fatty acid synthesis, leading to reduction in stored fat. Conclusions: This study concludes that ketone bodies obtained from ketogenic diets may serve as an adjuvant therapy in the management of obesity with a reduced risk of toxicity compared with conventional therapy.

Novel spiro[chromanone-2,4′-piperidine]-4-one derivatives as potential inhibitors of fatty acid synthesis in pathogens: Design, synthesis, and biological evaluation

Bacterial survival depends on membrane lipid homeostasis that enables to regulate lipid composition to adapt and optimize their growth in diverse environments. Therefore, the development of inhibitors that interfere with the bacterial fatty acid synthesis process is considered to be a promising tactic. In this study, 58 novel spirochromanone derivatives were prepared and their structure–activity relationship (SAR) was investigated. The bioassay results showed that all most of the compounds showed excellent biological activities, exampled by compounds B14, C1, B15, and B13, which had outstanding inhibitory activities toward various pathogenic bacteria with EC50 values of 0.78 μg/mL ∼3.48 μg/mL. Preliminary antibacterial behavior was studied by a series of biochemical assays including, but not limited to, fluorescence imaging patterns, GC-MS analysis, TEM images, and fluorescence titration experiments. Notably, compound B14 decreased the lipid content of the cell membrane, and increased cell membrane permeability, thereby destroying the integrity of the bacterial cell membrane. Further qRT-PCR results indicated that compound B14 interfered with the mRNA expression levels of fatty acid synthesis process-related genes including ACC, ACP, and Fab family genes. Herein, we highlight the promising bactericidal skeleton based on the spiro[chromanone-2,4′-piperidine]-4-one as a potential inhibitor of fatty acid synthesis.

Effectiveness of using the mixtures of herbicides flumioxazine and fluorochloridone in sunflower crops

Aim. This work is devoted to the search for potential partners for the integrated application of flumioxazine in sunflower crops. This herbicide is an inhibitor of protoporphyrinogen oxidase (PPO) in weed plants. The resistance to this class of herbicides is not yet common today, compared to other classes. Therefore, the work is aimed at de- veloping flumioxazine-based herbicide compositions that effectively prevent the emergence of herbicide-resistant weed biotypes. Methods. The interaction effects, weed control efficiency, and crop selectivity were studied when flumioxazine was used in the mixtures with herbicides acetochlor and propisochlor (long-chain fatty acid synthesis (LCFAS) inhibitors), promethrin (electron transport (ET) inhibitor in photosystem 2 (PS 2) of chloroplasts) and fluorochloridone (inhibitor of carotenoid synthesis by blocking the activity of phytoendesaturases (PDS)) both in the experiments on sunflower crops and in greenhouse experiments using the model objects. Results. The studies have shown that when flumioxazine is applied with the ET inhibitor, promethrin, the interaction is antagonistic, resulting in poor weed control efficiency and sunflower yield decrease. The tank mixtures of flumioxazine with LCFAS inhibitors acetochlor and propisochlor provide high weed control efficiency but are low in selectivity for sunflowers. The interaction between flumioxazine and fluorochloridone within the recommended application rates is additive. The tank mixture of flumioxazine and fluorochloridone herbicides at the application rates of 55 and 500 g/ha, respectively, is selective for sunflowers. In terms of control efficiency of annual dicotyledons, this mixture of herbicides exceeded, and in terms of control efficiency of annual cereal weed species was only slightly inferior to the control integrated herbicide (metolachlor + terbuthylazine). In these application rates, flumioxazine and fluo- rochloridone provided sunflower yield on par with this complex herbicide. Сonclusions. Among the investigated herbicides, the optimal partner of flumioxazine for complex use in sunflower crops was the herbicide, inhibitor PDS, fluorochloridone. Given that flumioxazine and fluorochloridone differ in their phytotoxicity mechanisms but share a common spectrum of controlled weed species, the use of a mixture of these herbicides is a factor that minimizes the likelihood of the emergence of herbicide-resistant weed biotypes.