Fatty Acid Synthesis Research Articles

TAp63γ is the primary isoform of TP63 for tumor suppression but not development

Abstract TP63 is expressed as TAp63 and ΔNp63 from the P1 and P2 promoters, respectively. While TAp63 and ΔNp63 are expressed as three TAp63α/β/γ and ΔNp63α/β/γ due to alternative splicing, only p63α (TA and ΔN) and p63γ (TA and ΔN) proteins are found to be detectable and likely to be responsible for p63-dependent activity. Previous studies implied and/or demonstrated that TAp63α, which contains an N-terminal activation domain conserved in p53, functions as a tumor suppressor by regulating an array of genes for growth suppression. By contrast, ΔNp63α, which also contains an N-terminal activation domain but is different from that in TAp63, regulates a unique set of genes and functions as a master regulator for development of epidermis and other stratified epithelial tissues. However, the biological function of p63γ is largely unexplored. To explore this, we generated a mouse model in that exon 10’, a coding exon specific for p63γ, was deleted by CRISPR-cas9. We showed that mice deficient in p63γ are viable and futile, which is different from mice deficient in total TP63 or p63α. Like TAp63-deficient mice, p63γ-deficient mice have a short lifespan and are prone to spontanenous tumors. Additionally, loss of p63γ shortens the lifespan of tumor-free mice potentially via increased cellular senescence. Moreover, mice deficient in p63γ are prone to chronic inflammation in multiple organs and liver steatosis potentially via altered lipid metabolism. Single-cell RNA-seq revealed that loss of p63γ increases the expression of SCD1, a rate-limiting enzyme for synthesis of monounsaturated fatty acids, leading to altered lipid homeostasis. Together, our data indicate that TP63γ is the primary isoform of TP63 for tumor suppression but not development by maintaining normal inflammatory response and lipid homeostasis.

Fishing for Solutions: How Pre-Conceptional Fish Oil Supplementation in Obese Fathers Reduces Risk of Non-Alcoholic Fatty Liver Disease in Offspring Mice.

Metabolic dysfunction associated fatty liver disease (MAFLD) is a chronic condition with hepatic fat accumulation. The intergenerational effect of obesity has predominantly focused on mothers, with limited studies on paternal obesity. Nutritional intervention with fish oil (FO) has beneficial effects in reducing markers of obesity. We hypothesized that supplementing obese fathers with FO before conception could enhance the metabolic health of their offspring liver. Male mice were assigned to low-fat (LF), high fat (HF), or HF supplemented with FO for 10 weeks. Subsequently, these males were mated with females on a chow diet. Offspring were sacrificed at 8 weeks, and liver tissues were analyzed for gene expression and histology. Offspring body weight was not significantly impacted by paternal diet. However, male offspring of HF fathers had higher levels of markers of inflammation and fatty acid synthesis compared to offspring of LF fed fathers. Paternal FO supplementation significantly reduced fatty acid synthesis and glucose metabolism, while increasing fatty acid oxidation in male offspring, with a less pronounced effect in female offspring. These findings suggest that FO supplementation in obese fathers prior to conception attenuates the development of MAFLD in male offspring. This data underscores the significance of paternal nutritional intervention in promoting offspring health.

Cannabidiol attenuates lipid metabolism and induces CB1 receptor-mediated ER stress associated apoptosis in ovarian cancer cells

Ovarian cancer (OC) is the most deadly gynecological tumor. OC cells utilize cellular metabolic reprogramming to gain a survival advantage, particularly through aberrant lipid metabolic process. As the primary ingredient in exogenous cannabinoids, cannabidiol (CBD) has been confirmed to exhibit antitumor activity in preclinical studies. However, it is still unclear whether CBD can disrupt fatty acid metabolism and induce apoptosis in OC cells. In this study, we have demonstrated that CBD significantly inhibits the proliferation of OCs through a cannabinoid receptor type 1 (CB1R)-mediated manner. Fatty acid metabolic profiling and flow cytometry analysis revealed that CBD has the ability to decrease fatty acid levels and significantly suppress the transcription of genes involved in fatty acid uptake and synthesis in ES-2 cells. In addition, the analysis from RNA-seq and real-time RT-PCR revealed that CBD activated the endoplasmic reticulum (ER) stress pathway. Conversely, by supplementation with unsaturated fatty acid or blocking CB1R, ER stress or reactive oxygen species (ROS) signals with specific inhibitors could significantly relieve CBD induced, dose-dependent, ER stress associated apoptosis, G0-G1 phase arrest, and mitochondrial dysfunction. Taken collectively, these data indicate that CBD may disrupt lipid metabolism, and lead to ER stress-related apoptosis in OCs. Our findings may provide a theoretical mechanism for anti-ovarian cancer using CBD.

GLP1 alleviates oleic acid-propelled lipocalin-2 generation by tumor-infiltrating CD8+ T cells to reduce polymorphonuclear MDSC recruitment and enhances viral immunotherapy in pancreatic cancer.

Recruitment of polymorphonuclear MDSCs (PMN-MDSCs) in the TME suppresses the antitumor activity of tumor-infiltrating CD8+ T cells (CD8+ TILs). Little is known about the role of antitumoral CD8+ TILs in actively initiating an immune-tolerant microenvironment, particularly in the recruitment of PMN-MDSCs. In this study, we found that immunotherapy-activated CD8+ TILs significantly increased PNM-MDSC infiltration in the TME, resulting in antitumor resistance. When CD8+ T cells are activated, lipocalin-2 (LCN2) expression is strongly upregulated, which significantly enhances PMN-MDSC chemotaxis. Mechanistically, immune activation increased fatty acid synthesis in CD8+ T cells, particularly oleic acid (OA), which induced lysosomal membrane permeabilization, releasing cathepsin B and subsequently activating NF-κB to promote LCN2 expression. Moreover, we showed that glucagon-like peptide 1 (GLP1) effectively inhibited OA synthesis in activated CD8+ T cells, reducing LCN2 production. We then developed a recombinant adenovirus encoding GLP1 (AdV-GLP1), which significantly reduced PMN-MDSC infiltration and reinvigorated the antitumor activity of CD8+ TILs. In various pancreatic cancer models, including subcutaneous, orthotopic, and humanized CDX/PDX models, AdV-GLP1 displayed excellent antitumor efficacy. Our work advances the understanding of how immunotherapy-activated CD8+ TILs initiate PMN-MDSC infiltration and provides a clinically relevant strategy to target this interaction and improve cancer immunotherapy.

Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia

BackgroundSignificant sex differences exist in the prevalence and incidence of Alzheimer’s disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.MethodsMicroglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.ResultsSex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.ConclusionsThese findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.

NPD7426 suppresses sterol regulatory element-binding proteins by promoting the degradation of mature SREBP forms.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate various genes involved in cholesterol and fatty acid synthesis, playing a central role in lipid metabolism regulation in vivo. SREBP-1c activity is significantly elevated in the liver under conditions of obesity, fatty liver disease, and type II diabetes, while suppression of SREBP-1c activity has been shown to alleviate these symptoms. Consequently, targeting SREBP-1c activity is considered a potential therapeutic approach for these conditions. In this study, we identified NPD7426 as a compound with inhibitory effects on SREBP activity. Furthermore, we demonstrated that NPD7426 promotes the proteasome-mediated degradation of mature SREBP protein forms. These findings provide new insights into the mechanism of SREBP activity suppression by small-molecule compounds containing NPD7426, suggesting that NPD7426 may be a promising candidate for the development of therapeutic drugs targeting SREBPs.

Short-Term Metformin Protects Against Glucocorticoid-Induced Toxicity in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Trial.

Glucocorticoids (GCs) are potent anti-inflammatory drugs, but strategies to prevent side effects are lacking. We investigated whether metformin could prevent GC-related toxicity and explored the underlying mechanisms. This single-center, randomized, placebo-controlled, double-blind, crossover trial compared metformin with placebo during high-dose GC treatment in 18 lean, healthy, male study participants. The trial was conducted at the University Hospital Basel, Switzerland. Participants received prednisone 30 mg/d in combination with metformin or placebo for two 7-day periods (1:1 randomization). The primary outcome, change in insulin sensitivity, was assessed using a two-sided paired t test. Before and after each study period, we conducted a mixed-meal tolerance test, blood metabolomics, and RNA sequencing of subcutaneous adipose tissue biopsy specimens. Metformin improved insulin sensitivity as assessed by the Matsuda index (n = 17; mean change: -2.73 ± 3.55 SD for placebo, 2.21 ± 3.95 for metformin; mean difference of change -4.94 [95% CI, -7.24, -2.65)]; P < 0.001). Metabolomic and transcriptomic analyses revealed that metformin altered fatty acid flux in the blood and downregulated genes involved in fatty acid synthesis in adipose tissue. Metformin reduced markers of protein breakdown and bone resorption. Furthermore, metformin downregulated genes responsible for AMPK inhibition and affected GLP1 and bile acid metabolism. Metformin prevents GC-induced insulin resistance and reduces markers of dyslipidemia, myopathy, and, possibly, bone resorption through AMPK-dependent and -independent pathways.

Metabolomics, network pharmacology, and microbiome analyses uncover the mechanisms of the Chinese herbal formula for the improvement of meat quality in spent hens

BackgroundMeat originating from the spent hen is an important source of poultry meat production; however, multiple factors cause the decline in the meat quality of spent hens. Chinese herbs have been widely used as medicine for a long time to prevent diseases and as nutrient supplements to improve the product quality. This experiment explored the effects of adding 1.0% Chinese herbal formula (CHF, including 0.30% Leonurus japonicus Houtt., 0.20% Salvia miltiorrhiza Bge., 0.25% Ligustrum lucidum Ait., and 0.25% Taraxacum mongolicum Hand.-Mazz.) for 120 d to the spent hens’ diet through metabolomics, network pharmacology, and microbiome strategies.ResultsThe results indicated that CHF supplementation improved the meat quality by reducing drip loss (P < 0.05), b* value (P = 0.058), and shear force (P = 0.099) and increasing cooked meat percentage (P = 0.054) and dry matter (P < 0.05) of breast muscle. The addition of CHF improved the nutritional value of breast muscle by increasing (P < 0.05) the content of C18:2n-6, n-6/n-3 polyunsaturated fatty acids (PUFA), total PUFA, PUFA-to-saturated fatty acids (SFA) ratio, and hypocholesterolemic-to-hypercholesterolemic ratio, and tending to increase serine content (P = 0.069). The targeted metabolomics analysis revealed that the biosynthesis of SFA, linoleic acid metabolism, fatty acid degradation, fatty acid elongation, and fatty acid biosynthesis pathways were enriched by CHF supplementation. Furthermore, the network pharmacology analysis indicated that CHF was closely associated with oxidative stress and lipid metabolism. The CHF supplementation increased the glutathione peroxidase level (P < 0.05) and upregulated gene expression related to the Nrf2 pathway (including HO-1, P < 0.05; Nrf2, P = 0.098; CAT, P = 0.060; GPX1, P = 0.063; and SOD2, P = 0.052) and lipid metabolism (including PPARγ, P < 0.05; SREBP1, P = 0.059; and CPT1A, P = 0.058). Additionally, CHF supplementation increased Firmicutes and decreased Bacteroidetes, Spirochaetes, and Synergistetes abundances (P < 0.05), which may contribute to better meat quality.ConclusionsOur results suggest that CHF supplementation improved the quality and nutritional value of meat, which will provide a theoretical basis for the utilization of CHF as a feed additive in spent hens’ diets.Graphical

Efficient Escherichia coli Platform for Cannabinoid Precursor Olivetolic Acid Biosynthesis from Inexpensive Inputs.

Olivetolic acid (OLA), an initial precursor of cannabinoids, is catalyzed by type III polyketide synthase, which has a wide range of pharmacological activities, such as antimicrobial and cytotoxic effects. Here, we applied systematic metabolic engineering to develop a multienzyme cascade system to produce OLA via two low-cost inputs. The polyketide synthase (OLS) and cyclase enzymes (OAC), along with the best combination of hexanoyl-CoA and malonyl-CoA synthetases (AEE3 and MatB), were first introduced into the biocatalytic system to increase the supply of hexanoyl-CoA and malonyl-CoA as starting and extender units. To drive the catalysis smoothly, an ATP regeneration system and a CoA-sufficient supply system were incorporated into the biocatalysts to provide enough cofactors. Furthermore, malonyl-CoA flux was redirected to OLA biosynthesis through delicate control of the fatty acid biosynthesis (FAB) pathway via promoter engineering. Collectively, these strategies have led us to produce OLA at a titer of 102.1 mg/L with a productivity of 25.5 mg/L/h by using malonate and hexanoate as direct substrates. Our biocatalytic system provides an effective platform for the production of the cannabinoid precursor OLA in Escherichia coli and may be a valuable reference for the development of microbial cell factories that use hexanoyl-CoA and malonyl-CoA as important intermediates.

Specialized genera and niche partitioning promote the biosynthesis of short-chain fatty acids in anaerobic cofermentation of sewage sludge and protein-rich waste.

Elucidating the relationships among various microorganisms and their reactions to environmental fluctuations, such as dissolved organic matter (DOM), remains a key objective in the anaerobic cofermentation (ACF) of sewage sludge (SS) and protein-rich waste (PRW); however, this topic is inadequately understood. In this study, the microbial traits associated with the biosynthesis of short-chain fatty acids (SCFAs) were investigated in the ACF of SS in conjunction with four distinct PRWs (pupa, fishmeal, maize gluten, and soybean meal). Compared with those in the SS-only reactor, the first-order rate constants for biosolid dissolution in the SS/PRW reactors were increased by 1.9-4.0-fold. Pupa performed best among the four PRWs in the ACF process, with the solubilization rate increasing from 9.4% (SS-only reactor) to 33.5%. The copious and readily biodegradable DOM created a unique niche for functional microbes, leading to reframing of the microfloral structure. Specialized genera, such as Holophaga, Alistipes, and Geothrix, were responsible for SCFA biosynthesis in the SS/pupa reactor. The highly differentiated, low-redundancy microecosystem constructed in the SS/pupa reactor contributed to the independent functioning of the hydrolyzers and acidogens, resulting in an SCFA yield that was 6.9-fold greater than that in the SS-only reactor. In addition, the ACF of SS/pupa resulted in the genes encoding the NiFe hydrogenase and Wood-Ljungdahl pathway being intact, which promoted the synthesis of SCFAs, especially acetate. These findings offer new insights into the microbiological mechanisms that augment SCFA generation by the ACF of SS/PRW in terms of microorganism fate, metabolic network relationships, and microecosystem niche.

Integrated bioinformatics and multi-omics to investigate the mechanism of Rhododendron molle Flos-induced hepatotoxicity.

Drug-induced liver injury (DILI) is an important and common adverse drug event. Rhododendron molle Flos (RMF), as one of toxic Traditional Chinese medicines (TCMs), holds a prominent position in clinical practice for treating rheumatoid arthritis. However, the toxicity of RMF limits its safe. Most of the concerns are about its rapid neurotoxicity and cardiotoxicity, with less attention paid to its hepatotoxicity, and the mechanism of which is still unclear. To reveal the mechanism of RMF-induced hepatotoxicity by bioinformatics and multi-omics. Rats were intragastric administered RMF at doses of 0.8g/kg, 0.4g/kg, and 0.2g/kg once daily for 2 weeks. Initially, hepatotoxicity was then evaluated using liver function enzymes, antioxidant enzymes, and histopathology. Subsequently, network toxicology, transcriptomics, and metabolomics were used to identify the genes and metabolites. In addition, molecular docking and Western blot were employed to verify toxic components and key targets. RMF caused abnormal levels of ALT, γ-GT, TBIL, and TBA in the serum of rats, as well as abnormal levels of MDA, GSH-Px, and SOD in the liver, leading to inflammatory infiltration of liver cells, with a dose-dependent manner. RMF disordered the steroid hormone biosynthesis, pyruvate metabolism, fatty acid biosynthesis, and arachidonic acid metabolism. Six key targets were identified- UGT1A6, CYP2E1, ACOT1, ACSL5, CTH, and PKLR, along with their corresponding metabolites, namely 17β-estradiol, estriol, arachidonic acid, octadecanoic acid, and pyruvic acid. The hepatotoxicity could be attributed to five diterpenoid components, including grayanotoxin-III, rhodojaponin (RJ)-I, RJ-II, RJ-III, and RJ-V. This study comprehensively identified the toxic components, upstream targets, and downstream metabolites of RMF-induced liver toxicity, providing a basis for evaluating and monitoring liver function in patients during clinical application.

Transcriptomic Signature of Lipid Production in Australian Aurantiochytrium sp. TC20.

Aurantiochytrium not only excels in producing long-chain polyunsaturated fatty acids such as docosahexaenoic acid for humans, but it is also a source of essential fatty acids with minimal impacts on wild fisheries and is vital in the transfer of atmospheric carbon to oceanic carbon sinks and cycles. This study aims to unveil the systems biology of lipid production in the Australian Aurantiochytrium sp. TC20 by comparing the transcriptomic profiles under optimal growth conditions with increased fatty acid production from the early (Day 1) to late exponential growth phase (Day 3). Particular attention was paid to 227 manually annotated genes involved in lipid metabolism, such as FAS (fatty acid synthetase) and subunits of polyunsaturated fatty acids (PUFA) synthase. PCA analysis showed that differentially expressed genes, related to lipid metabolism, efficiently discriminated Day 3 samples from Day 1, highlighting the key robustness of the developed lipid-biosynthesis signature. Highly significant (pFDR < 0.01) upregulation of polyunsaturated fatty acid synthase subunit B (PFAB) involved in fatty acid synthesis, lipid droplet protein (TLDP) involved in TAG-synthesis, and phosphoglycerate mutase (PGAM-2) involved in glycolysis and gluconeogenesis were observed. KEGG enrichment analysis highlighted significant enrichment of the biosynthesis of unsaturated fatty acids (pFDR < 0.01) and carbon metabolism pathways (pFDR < 0.01). This study provides a comprehensive overview of the transcriptional landscape of Australian Aurantiochytrium sp. TC20 in the process of fatty acid production.

Impact of expression of metabolic genes on patient (pts) outcomes in metastatic colorectal cancer (mCRC): Data from CALGB/SWOG 80405 (Alliance).

224 Background: Metabolic pathways are reprogrammed during CRC development, leading to increased glycolysis, glutaminolysis, and fatty acid synthesis. Understanding the impact of metabolic reprogramming on treatment outcomes is paramount. Hence, we investigated whether the tumor gene expression of 4 selected major metabolic genes ( PKM, SLC2A1 , SLC16A1 , and CAV1 ) could affect treatment response in pts enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of gene expression (high [H], medium [M] and low [L]). Logrank P -values provide a non-parametric unadjusted assessment of differences. Likelihood ratio tests (LRT) were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ECOG, tumor side, number of metastatic sites, KRAS , CMS, and treatment. Results: PKM gene expression was associated with cet treatment outcomes with PKM- low tumors showing significantly longer PFS and OS (median PFS: 14.3 vs 9.8 vs 8.1 months, L vs M vs H, P &lt; 0.0001, LRT P = 0.011; median OS: 45.9 vs 31.2 vs 20.9 months, P &lt; 0.0001, LRT P = 0.12). Low SLC2A1 was also associated with longer OS in cet-treated pts (32.4 vs 35.8 vs 25.2 months, P = 0.02, LRT P &lt; 0.0001). Similar results were observed in bev-treated pts where low SLC2A1 expressing tumors had longer OS (37.4 vs 26.1 vs 29 months, P = 0.037, LRT P = 0.069) and a non-significant trend for longer PFS (13.1 vs 11 vs 9.5 months, P = 0.076). CAV1 low gene expression was associated with longer OS in cet-treated pts (37.4 vs 34 vs 21.5 months, P = 0.0048, LRT P = 0.013), while no significant associations were found in bev-treated (interaction LRT P = 0.0009). No significant results were observed for SLC16A1 . Conclusions: The intratumoral expression of metabolic genes was prognostic and predictive in mCRC pts treated with first-line therapy. GLUT1 (encoded by SLC2A1 ) and PKM2 (encoded by PKM ) promote aerobic glycolysis of cancer cells, known as Warburg effect, supporting rapid cell proliferation and survival. CAV1 has been shown to be involved in mitochondrial bioenergetics and fatty acid metabolism and to play either a tumor suppressor or oncogenic role depending on the cancer type and stage. Lower expression of SLC2A1 and PKM was associated with improved survival and increased benefit from cet treatment in our cohort. Low CAV1 expression was also associated with increase survival suggesting a cancer-promoting role in mCRC. Our results suggest that targeting cancer cell metabolism through novel inhibitors of the aforementioned pathways may be a promising therapeutic strategy.

Synthesis, Antibacterial Activity and In Silico Study of 1-(2-ethyl acetate)-2-styryl 5-nitroimidazole Derivatives

Background: For more than six decades, the use of metronidazole has been limited to anaerobic microorganisms. However, there are accounts of metronidazole derivatives exhibiting strong effectiveness against facultative anaerobic bacteria, suggesting that there may be another mechanism of action for metronidazole. Recent studies have shown that the enzyme FabH (β-ketoacyl-acyl carrier protein synthase III), responsible for the first step of fatty acid biosynthesis (FAB), is a promising target for nitroimidazole derivatives that can be used as an effective anti-infective agent. Objective: This study aimed to synthesize 1-(2-ethyl acetate)-2-styryl nitroimidazole derivatives and evaluate their in vitro and in silico antibacterial activity Methods: We synthesized 2-styryl 5-nitroimidazole derivatives by first condensing metronidazole with benzaldehydes and then carrying out an acetylation reaction. We evaluated the antimicrobial activity of the synthesized compounds against three Gram-positive bacterial strains (Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus agalactiae) and three Gram-negative bacterial strains (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae) using a two-fold serial dilution MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assay. Results: Compounds 2 and 4 exhibited the highest level of antibacterial effectiveness, with minimum inhibitory concentrations (MIC) of 1.56 μg/mL against S. agalactiae and 3.13 μg/mL against P. aeruginosa. Compounds 2 and 4 also exhibited potent activity against K. pneumonia, with an MIC value of 6.25 μg/mL and 12.5 μg/mL, respectively. Molecular docking studies revealed that both compounds have favorable hydrophobic and electrostatic interactions with conserved residues in the binding site of the E. coli β-Ketoacyl-acyl carrier protein synthase III (FabH) complex. Conclusion:: Acetylation of 2-styryl-5-nitroimidazoles improved both their biological activity and binding interaction with the target protein

Metabolome-Wide Mendelian Randomization Assessing the Causal Relationship Between Blood Metabolites and Primary Ovarian Insufficiency

Background & aimsPrimary ovarian insufficiency (POI) is a significant clinical syndrome that leads to female infertility, and its incidence continues to increase. We used metabolome-specific Mendelian randomization (MR) to identify causally associated metabolites and explore the relationship between candidate metabolites and upstream genetic variations. MethodsThe primary MR analysis utilized the inverse variance weighted (IVW) method as the primary approach to assess the causal relationship between exposure and POI. Multiple sensitivity analyses included MR-Egger, weighted median, and weighted mode methods. ResultsAfter using genetic variants as probes, we identified 27 metabolites of 278 that are associated with the risk of POI, including dodecanedioate (OR 0.052, 95% CI 0.010 – 0.265; P < 0.001), adrenate (OR 0.113, 95% CI 0.016 – 0.822; P = 0.031), indolepropionate (OR 0.174, 95% CI 0.051 – 0.593; P = 0.005), homocitrulline (OR 0.194, 95% CI 0.051 – 0.741; P = 0.016), and 3-methylhistidine (OR 0.404, 95% CI 0.193 – 0.848; P = 0.017). Our study indicated the presence of heterogeneity; therefore, we employed the IVW random-effects model as the primary approach. KEGG pathway enrichment analysis identified six significant metabolic pathways, primarily including biosynthesis of unsaturated fatty acids, phenylalanine, tyrosine and tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, linoleic acid metabolism, valine, leucine and isoleucine biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis. ConclusionsBy integrating genomics and metabolomics, this study provides novel insights into the causal relationship linking circulating metabolites and the onset of POI.

Soybean bioactive peptide supplementation improves gut health and metabolism in broiler chickens.

This study aimed to investigate the effects of soybean bioactive peptide (SBP) on the growth performance and intestinal health of yellow-feathered broilers and to further elucidate the regulatory mechanisms of intestinal health using multi-omics analysis. A total of 320 1-day-old yellow-feathered broilers were randomly divided into two groups, with 10 replicates per group and 16 birds per replicate. Broilers in the control group received the basal diet, and those in the experimental group (SBPG) received the basal diet with 0.2 % SBP replacing the same amount of soybean meal. The experiment lasted for 70 d. The results showed that, compared with those in the control group, the final body weight and average daily gain of SBPG broilers were significantly higher (P < 0.05), and the feed conversion ratio was significantly lower (P < 0.05). Notably, SBP significantly improved gut health in chickens, including increased intestinal villus height, decreased levels of proinflammatory factors, such as IL-1β and interferon-γ, and upregulated expression of tight junction proteins, such as ZO-1 and occludin. In addition, transcriptome sequencing results revealed that broilers in the SBP group exhibited significant enrichment in multiple metabolic pathways, including fatty acid metabolism, fatty acid degradation, and the biosynthesis of unsaturated fatty acids (P < 0.05). Cecal 16S rRNA sequencing showed that SBPG increased the abundance of the butyrate-producing beneficial bacteria Muribaculaceae. Subsequent cecal metabolome analysis also revealed that SBPG enhanced lipid-related metabolic pathways, such as alpha-linolenic acid metabolism and GPI-anchor biosynthesis. In conclusion, SBP is a potential feed additive that can improve intestinal morphology, enhance intestinal immunity and barrier function, optimize the structure of the intestinal microbiota, and enhance metabolic function.

MtrAB two-component system is crucial for the intrinsic resistance and virulence of Mycobacterium abscessus.

Mycobacterium abscessus (Mab) poses serious therapeutic challenges, largely due to its intrinsic resistance to many antibiotics. The development of targeted therapeutic strategies necessitates the identification of bacterial factors that contribute to its reduced susceptibility to antibiotics and/or to the killing by its host cells. In this study, we discovered that Mab strains with disrupted mtrA, mtrB or both, or a gene-edited mtrA encoding MtrA with Tyr102Cys mutation, exhibited highly increased sensitivity to various drugs compared to the wild-type Mab. In a murine model, three antibiotics inactive against the wild-type Mab demonstrated efficacy against the mtrA and mtrB knockout strains, significantly reducing pulmonary bacterial burdens compared to untreated controls. Notably, the virulence of all the mtrA, mtrB and mtrAB knockout mutants was highly diminished, evidenced by a reduced bacterial load in mouse lungs, undetectable level in spleens, and defective growth in macrophage RAW264.7. Morphological analysis revealed elongated cell length and multiple septa in knockout strains, suggesting both MtrA and MtrB regulate cell division of Mab. Furthermore, the absence of mtrA, mtrB or both significantly increased cell envelope permeability and reduced biofilm formation. Transcriptome sequencing showed altered expression levels of multiple genes related to plasma membrane, fatty acid metabolism and biosynthesis pathways in wild-type Mab and mtrA knockout strain. In summary, this study suggests that MtrA and MtrB play a crucial role in the intrinsic resistance and virulence of Mab by affecting cell division and altering cell permeability. Consequently, MtrA and MtrB represent promising targets for the discovery of anti-Mab drugs.

Modulatory effect of Echium plantagineum oil on the n-3 LC-PUFA biosynthetic capacity of chicken (Gallus gallus).

Poultry can be a sustainable source of eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) through the bioconversion of dietary alpha-linolenic acid (ALA, 18:3n-3). However, this process is currently limited by the high n-6/n-3 ratio in poultry diets affecting the competition between n-6 and n-3 fatty acids (FA) for the same biosynthetic enzymes, and the rate-limiting Δ6 desaturase which act at both, the first and final steps of DHA synthesis pathway. Echium plantagineum oil (EO) is an unusual source of stearidonic acid (SDA, 18:4n-3) which bypasses the first Δ6 desaturase step potentially increasing n-3 long-chain polyunsaturated fatty acids (LC-PUFA) synthesis. To explore this hypothesis, 60 Canarian male chickens at 18 weeks of age were divided into three groups and fed diets differing only in their FA formulation: soy oil (SO) rich in linoleic acid (LA, 18:2n-6); linseed oil (LO) rich in ALA; and EO, a balanced LA/ALA oil also rich in SDA and γ-linolenic acid (GLA, 18:3n-6). The dietary treatments did not affect the total lipid (TL) content (p>0.05) and did not substantially vary the lipid class (LC) profiles in the brain, liver, intestine, and muscle tissues. However, the inclusion of LO and EO equally increased n-3 polyunsaturated fatty acids (PUFA) levels in the brain, liver, and intestine compared to animals fed with SO (p<0.05). Moreover, EO increased hepatic relative expressions of the fatty acid elongases (elovl2 and elovl5). Consequently, and in alignment with our hypothesis, EO was more effective than LO in enriching chicken thigh meat with n-3 LC-PUFA (6.0 vs 4.2%; p<0.05). We concluded that lowering the dietary LA/ALA ratio and increasing the SDA content in poultry diets enhance the potential of chicken metabolism for enriching poultry products with n-3 LC-PUFA. Emerging evidence suggest that local plants like those including in Echium genus, rich in SDA and with a balanced LA/ALA ratio, could offer a more sustainable and efficient alternative to traditional ALA sources in poultry production.

Biorefinery of sugarcane molasses for poly(3-hydroxybutyrate) fermentation and genomic elucidation of metabolic mechanism using Paracoccus sp. P2.

Biorefining sugarcane molasses to produce polyhydroxyalkanoates (PHAs) is an anticipated paradigm for replacing petroleum-based plastics. Nevertheless, there exists a deficiency in excellent chassis and genome resolution for the synthesis of poly(3-hydroxybutyrate) (PHB), which is a typical representative of PHAs. In this study, successive enrichment domestication was employed to screen PHB producers. The isolated species was defined as Paracoccus sp. P2 through taxonomic analysis. Then, a variety of nutrient substrates and physicochemical parameters were tailored to enhance the fermentation capacity. The maximum production of bio-polyester was 4.4 g·L-1, corresponding to a yield of 0.37 g-PHB·g-1-glucose. The concentration of PHB produced from 30 g·L-1 sugarcane molasses was 3.9 g·L-1, indicating a comparable fermentation performance. Furthermore, three-step condensation of acetyl-CoA and de novo synthesis of fatty acids were identified as the primary PHB accumulation pathways. The fermentation performance and genome investigation were compared with Paracoccus genus. The effective production of Paracoccus sp. P2 might be attributed to its efficient substrate conversion capacity and abundant PHB metabolic network. This study broadened the germplasm resources available for the bioconversion of sugarcane molasses, providing theoretical references for the valorization of high-concentration waste carbon sources.

Alterations in the Tongue Coating Microbiome in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Cross-Sectional Study.

The gut microbiota plays a critical role in the occurrence and development of IBS-D, however, IBS-D-associated tongue coating microbiome dysbiosis has not yet been clearly defined. To address this, we analyzed the structure and composition of the tongue coating microbiome in 23 IBS-D patients and 12 healthy controls using 16S rRNA high-throughput sequencing analysis. The 16S rRNA sequencing results revealed that the overall observed OTUs of tongue coating microbiome in IBS-D patients exhibited a significant decrease compared with the healthy controls. Alpha diversity analysis showed that the diversity and community richness were significantly reduced in IBS-D patients, and PCoA revealed a distinct clustering of tongue coating microbiome between the IBS-D patients and healthy controls. Microbial comparisons at the genus level showed that the abundance of Veillonella, Prevotella in IBS-D patients was higher than those in healthy controls, while Streptococcus, Haemophilus, Granulicatella, and Rothia were significantly reduced compared with the healthy volunteers. Functional analysis results showed significant differences in 88 functional metabolic pathways between the IBS-D patients and the healthy controls, including fatty acid biosynthesis. These findings identified the structure, composition, functionality of tongue coating microbiome in IBS-D patients, and hold promise the potential for therapeutic targets during IBS-D management.