PubMed

J Ethnopharmacol. 2024 Nov 21:119150. doi: 10.1016/j.jep.2024.119150. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum migao H.W. Li, commonly known as migao (MG), is used in the Miao region of China for treating cardiovascular and cerebrovascular diseases, attributed to its detoxifying (Jiedu in Chinese), blood-activating (Huoxue in Chinese), and Qi-promoting (Tongqi in Chinese) effects. However, the therapeutic potential of MG for ischemic stroke (IS) has yet to be explored. Therefore, this study was to explore the protective effect of MG against cerebral ischemia-reperfusion injury caused by IS.AIM OF THE STUDY: The aim of this study was to investigate whether ethanol extract of MG (EEMG) attenuates cerebral ischemia-reperfusion injury, and explored the underlying mechanisms.MATERIALS AND METHODS: Middle cerebral artery occlusion and reperfusion (MCAO/R) was established, and the efficacy of EEMG was evaluated using triphenyltetrazolium chloride (TTC), immunofluorescence, hematoxylin-eosin staining (HE) staining, and real-time quantitative PCR (qRT-PCR). Qualitative analysis of EEMG was analyzed for chemical composition by liquid chromatography-mass spectrometry (LC-MS). The molecular mechanism of EEMG was explored by metabolomics, network pharmacology, immunoblotting, immunofluorescence staining, gene knockdown, and agonist treatment.RESULTS: The results showed that EEMG can alleviate ischemic injury in MCAO/R-operated rats and neuronal damage of OGD/R-treated SH-SY5Y cells. Specifically, EEHGT inhibited the release of inflammatory factors and reversed serum metabolic profile disorders of MCAO/R rats. Network pharmacology analysis showed that the PI3K-Akt and NF-κB signaling pathways maybe involved in EEMG-mediated neuroprotective effects on ischemic injury and inhibition of inflammatory response. As we expected, EEMG can activate PI3K-AKT and suppress NF-kB signaling pathways both in MCAO/R-operated rats and OGD/R-treated BV2 cells. The results showed that knockdown of TLR4 abolished the EEMG-mediated inhibition on neuroinflammation in OGD/R-treated BV2 cells. After treating BV2 cells with the TLR4 agonist neoseptin 3, EEMG showed a trend toward inhibiting neuroinflammation but with no significant difference. Additionally, EEMG was found to improve liver injury caused by cerebral ischemia-reperfusion and associated with NF-κB signaling pathway in this study.CONCLUSIONS: Collectively, this study demonstrated that EEMG attenuates neuroinflammation in cerebral ischemia-reperfusion injury via regulating TLR4-PI3K-Akt-NF-κB pathways.PMID:39580135 | DOI:10.1016/j.jep.2024.119150

Chem Biol Interact. 2024 Nov 21:111315. doi: 10.1016/j.cbi.2024.111315. Online ahead of print.ABSTRACTArticaine (ATC) has emerged as one of the most popular local anesthetics (LA) in dental clinics, despite its relatively recent introduction to the market. As a member of the amino-amide class of LA, ATC possesses unique features, including a thiophene ring and an ester group, which allow for its use at higher clinical concentrations. However, reports have indicated a higher incidence of paresthesia associated with ATC, though the underlying cause of this effect remains unclear. To investigate this further, we conducted an extracellular metabolic flux analysis and an NMR-based metabolomics study of ATC effects on Schwann cells - a type of glial cell found in the peripheral nervous system - in comparison to lidocaine (LDC), the "gold standard" LA in dentistry. The results showed that ATC had a more significant impact on Schwann cell oxygen consumption compared to LDC. Metabolomics profiling of Schwann cells revealed distinct metabolic alterations between the two treatments. Notably, ATC triggered elevated intracellular levels of various amino acids, including leucine, isoleucine, valine, phenylalanine, methionine, histidine, tyrosine, and glycine, which were not observed in LDC-treated Schwann cells. This was consistent with signs of endoplasmic reticulum stress and apoptosis in ATC-treated cells, as detected by protein expression analysis. These findings offer insights into the metabolic and cellular responses elicited by the two anesthetics in Schwann cells, that may help explain the differential toxicity and higher incidence of paresthesia associated with ATC.PMID:39580065 | DOI:10.1016/j.cbi.2024.111315

Food Chem Toxicol. 2024 Nov 21:115125. doi: 10.1016/j.fct.2024.115125. Online ahead of print.ABSTRACTPolyethylene terephthalate microplastics (PET-MPs) have emerged as significant environmental pollutants with potential health risks. This study investigates the cytotoxic effects of PET-MPs on BEAS-2B lung epithelial cells through integrated transcriptomic and metabolomic analyses. The results of the CCK8 assay showed a reduction in the viability of BEAS-2B cells following continuous exposure to PET-MPs. Transcriptomic analysis identified 1,412 differentially expressed genes (DEGs) mainly enriched in apoptosis and extracellular matrix organization processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these DEGs are predominantly involved in the PI3K-Akt, TNF, and MAPK signaling pathways. Metabolomic analysis identified 2,869 differentially expressed metabolites (DEMs), mainly associated with pyrimidine, arginine, proline, and β-alanine metabolism pathways. Multi-omics analysis indicated that PET-MPs primarily disrupt lipid metabolism, which may lead to an increased risk of apoptosis. We hypothesize that PET-MPs affect lipid metabolism by up-regulating the ANGPTL4 gene, thereby promoting cellular apoptosis. This study reveals the mechanisms of PET-MPs toxicity, emphasizing the potential risks they pose to human health.PMID:39580014 | DOI:10.1016/j.fct.2024.115125

Sci Total Environ. 2024 Nov 21:177669. doi: 10.1016/j.scitotenv.2024.177669. Online ahead of print.ABSTRACTBiodegradable microplastics (BMPs) may impact the environmental fate and ecotoxicity of Cd, but the effect mechanism in soil-plant system remain poorly understood. This study investigated the impact of BMPs (poly(lactic acid) (PLA) and poly(butylene adipate terephthalate) (PBAT) microplastics) on the Cd toxicity, translocation, transformation, and metabolome in lettuce (Lactuca sativa L.) by pot experiments. The results show that co-exposure to BMPs and Cd synergistically inhibited the shoot growth. 0.2 % PLA MPs enhanced but 2.5 % PLA MPs inhibited the photosynthesis; however, the dose of PBAT MPs was negatively correlated with the content of chlorophyll a. Moreover, the presence of 2.5 % PBAT MPs increased the nitrate content of leaves by 9.5 % compared to single Cd exposure. The partial least squares path model (PLS-PM) indicates that BMPs exacerbated the inhibitory effects of Cd on lettuce growth. PLA MPs enhanced K, Ca, Cu, and Zn accumulation in root stele, whereas PBAT MPs promoted Fe and Mn enrichment in epidermis. Furthermore, co-exposure resulted in higher inorganic and water-soluble Cd proportions in shoots. PLA MPs elevated Cd contents in cell wall fractions of both roots and shoots, while PBAT MPs increased Cd contents in shoot cell walls and root cells and soluble Cd ratio in shoots. BMPs enhanced Cd toxicity and bioaccumulation by downregulating the expression of ABC transporters and phenylpropanoid biosynthesis pathways, and the relative abundance of related metabolites.PMID:39579896 | DOI:10.1016/j.scitotenv.2024.177669

Sci Total Environ. 2024 Nov 21:177509. doi: 10.1016/j.scitotenv.2024.177509. Online ahead of print.ABSTRACTOffshore wind farms (OWFs) pose new anthropogenic pressures on the marine environment as the erosion of turbine blades release organic and inorganic substances with potential consequences for marine life. In the present study, possible effects of the released particles and their chemical constituents on the metabolic profile of the blue mussel, Mytilus edulis, were investigated, utilizing 1H NMR spectroscopy. In the lab, mussels were exposed for 7 and 14 days to different concentrations (10 and 40 mg/L) of microplastic (MP) particles which were derived from cryo-milled rotor blade coatings and core materials (glass fiber polymer, GFP). Raman imaging techniques revealed that 30-40 % of the coating and GFP particles had MP sizes below 5 μm, with the majority (~98 %) being ≤50 μm. Despite the identified enrichment factors (EF) for metals and metalloids from the rotor blade materials, especially Ba, Cu, Cd, Cr and Ni with EFs between 0.93 and 6.1, untargeted metabolic profiling of the entire soft body tissues of M. edulis showed no significant metabolic disruption, regardless of the particle concentration. Observed trends in elevated concentrations of metabolites may indicate a possible short-term effect on mussels' neuroendocrine system and a possible long-term effect on energy metabolism. Experimental worst-case scenario of massive abrasion and the minimal response observed in M. edulis under the conditions tested suggest that erosion caused by wind turbine blades may pose little to no risk to bivalves at this stage. However, it is important to note that this study is only a preliminary step and further studies are needed to obtain a comprehensive overview of the issue before reaching a definite firm conclusion regarding the potential threat of OWFs abrasion to the marine environment, particularly considering the planned future extension of windpark construction in connection with the ongoing EU-wide energy transition.PMID:39579893 | DOI:10.1016/j.scitotenv.2024.177509

Int J Biol Macromol. 2024 Nov 21:137928. doi: 10.1016/j.ijbiomac.2024.137928. Online ahead of print.ABSTRACTThe fungal pathogen Setosphaeria turcica (S. turcica) causes northern corn leaf blight (NCLB), resulting in significant yield and economic losses in maize. To elucidate the metabolic pathways essential for its pathogenicity, we investigated the metabolome of S. turcica during appressorium development, a critical stage for host infection. Our analysis indicated a substantial enrichment of sphingosine and related compounds during this phase. The application of chemical inhibitors to disrupt sphingolipid metabolism confirmed their pivotal role in appressorium formation and pathogenicity. Additionally, silencing of the serine palmitoyl transferase (Spt) core subunit gene StLCB2 led to significant alterations in fungal morphology and growth, accompanied by changes in cell membrane integrity, surface hydrophobicity, melanin, and sphingosine synthesis. These findings underscore the importance of sphingolipids in the pathogenicity of S. turcica and suggest that targeting specific components of the sphingolipid pathway could aid in developing novel fungicides or genetically engineered maize varieties with increased resistance to NCLB.PMID:39579824 | DOI:10.1016/j.ijbiomac.2024.137928

Plant Physiol Biochem. 2024 Nov 19;218:109302. doi: 10.1016/j.plaphy.2024.109302. Online ahead of print.ABSTRACTAlfalfa is a valuable forage crop but voluntarily affected by drought. Understanding the mechanisms of drought resistance in alfalfa is crucial for improving resilient cultivars. In our study, we used four distinct alfalfa accessions two drought-tolerance (DT) and two drought-sensitive (DS) and identified transcriptional modules and candidate genes associated with the drought tolerance in the DS from transcriptomic analyses. Our metabolic profiling of 520 metabolites revealed significant variations between the DS and DT groups, particularly in the levels of flavonoids and nucleotides and their derivatives. The integrated analysis of transcriptome and metabolome analysis revealed that the glycine, serine, and threonine metabolism and the sphingolipid metabolism are associated with the drought resistance. When drought stress occurs, MsSRR (MsG 0180002649.01) and MsSPHK1 (MsG 0280006618.01) are significantly up-regulated, L-serine and dihydrosphingosine (DHS) significantly down-regulated in DS. By silencing the MsSPHK1 gene we found the drought resistance was significantly improved. This was evidenced by a significant increase in the activity of antioxidant enzymes such as SOD, POD, and CAT, compared to the control group. Additionally, the photosynthetic rate, stomatal conductance, and efficiency of photosystem II measured by Fv/Fm, phi2 and qL, were significantly higher in the silenced plants than in the control group. In conclusion, our results suggest that the increased level of dihydrosphingosine improves alfalfa resistance to drought stress. Moreover, the negative regulatory role of MsSPHK1 in drought tolerance provides a promising target for genetic manipulation to enhance the resilience of alfalfa to drought stress.PMID:39579717 | DOI:10.1016/j.plaphy.2024.109302

Phytomedicine. 2024 Nov 15;136:156259. doi: 10.1016/j.phymed.2024.156259. Online ahead of print.ABSTRACTAIM OF THE STUDY: To evaluate the therapeutic mechanism of Honey-fried licorice on arrhythmia, to explore the distribution of main components of Honey-fried licorice in vivo before and after processing, and to elucidate the active ingredient of Honey-fried licorice on arrhythmia.MATERIALS AND METHODS: UPLC-Q-TOF/MS were used to analyze the common and different components of raw and honey-fried licorice before and after processing. Yin deficiency syndrome was established by continuous irritability and water platform sleep deprivation, and then ventricular arrhythmia model was established by injection of calcium chloride into the tail vein. Applying the electrocardiograph changes in heart rate in rats. Subsequently, ELISA and histopathological examinations were conducted to assess the therapeutic effects of honey-fried licorice on arrhythmia. Metabonomics analysis was employed to predict key regulatory pathways involved in the treatment response. Finally, RT-PCR and enzyme activity assays were utilized to verify the expression and function of key genes and proteins, providing insights into the underlying mechanisms.RESULTS: The heart rate of rats increased after injection of Cacl2 solution into the tail vein. Honey-fried licorice has a certain improvement effect on heart injury and tachycardia, and its mechanism may be through the obvious correction effect on SOD, MDA, LDH, Na+-K+-ATPase, CaM and CAMK2 in the arrhythmia model. Under pathological conditions, Metabonomics revealed that the heart was highly exposed to glycyrrhetic acid 3-O-glucuronide, isoformononetin, araboglycyrrhizin, 18β-glycyrrhetinic acid, liquiritigenin, licoflavonol and isoliquiritigenin are known to have anti-arrhythmic effects through immune regulation and oxidation. Notably, both PCR and ELISA analyses indicated that honey-fried licorice may effectively treat arrhythmia, potentially through the modulation of the arachidonic acid pathway.CONCLUSION: These results suggested that honey-fried licorice could protect against arrhythmia and alleviate oxidative stress and tissue damage caused by arrhythmia. Through correlation analysis and metabolomics, it was found that glycyrrhetic acid 3-O-glucuronide, isoformononetin, araboglycyrrhizin, 18β-glycyrrhetinic acid, liquiritigenin, licoflavonol and isoliquiritigenin can be used as the active ingredient of honey-fried licorice in the treatment of arrhythmia. Moreover, our results suggested that the therapeutic effect of honey-fried licorice on arrhythmia may be linked to the regulation of the arachidonic acid pathway. This study elucidates the mechanisms by which honey-fried licorice treats arrhythmia from a metabolic perspective, highlighting its role in "tonifying the spleen and stomach, supplementing qi, and replenishing the pulse." These findings provide a foundation for the further application of honey-fried licorice and the development of related products.PMID:39579611 | DOI:10.1016/j.phymed.2024.156259

Ecotoxicol Environ Saf. 2024 Nov 22;288:117378. doi: 10.1016/j.ecoenv.2024.117378. Online ahead of print.ABSTRACTThe global-scale production of plastics has led to a significant accumulation in the environment, and it has become a major stressor to environmental sustainability, agricultural crops, and human health. Here we report the particle size effect of polystyrene (PS, typically microplastic) on the impact on rice suspension cells. This study used PS of different particle sizes (30 nm, 200 nm, and 2 μm) in a three-day co-culture experiment, the results showed that 30 nm, 200 nm, and 2 μm PS at the same concentration (100 μg/mL) caused 4.6 %, 55.8 %, and 66.4 % decrease in rice suspension cell viability, respectively. Furthermore, a substantial reduction in protein content, amounting to 26.53 % and 48.47 %, was observed in cells treated with 200 nm and 2 μm PS, and the DNA and RNA content of rice suspension cells also decreased substantially at 100 μg/mL PS. Non-targeted metabolomics analyses showed that PS disrupted fatty acid biosynthesis with a clear size effect, wherein 2 μm PS caused a decrease of 64.9 % in hexadecanoic acid content. Consequently, this finding provides valuable perspectives on the potential ecotoxicity of microplastics at the single-cell level of rice and will facilitate the formulation of an environmental management program specifically tailored for addressing the challenges posed by microplastics.PMID:39579448 | DOI:10.1016/j.ecoenv.2024.117378

J Agric Food Chem. 2024 Nov 23. doi: 10.1021/acs.jafc.4c10093. Online ahead of print.ABSTRACTThe tea plant (Camellia sinensis) is a unique beverage crop worldwide, but its yield and quality are adversely affected by Toxoptera aurantii. However, the response mechanisms of tea plants to T. aurantii stress remain poorly known. Herein, we present the life table of T. aurantii on resistant (W016) and susceptible (HJY) tea cultivars, demonstrating that the fitness of T. aurantii on W016 was lower than that on HJY. Integrated metabolic and transcriptomic analyses revealed that T. aurantii feeding activated pathways associated with phenylpropanoid biosynthesis, plant hormone signal transduction, and ATP-binding cassette (ABC) transporters. Notably, T. aurantii feeding significantly upregulated the levels of brassinolide and p-coumaryl alcohol in W016 but not in HJY. Furthermore, in vitro enzymatic assays indicated that C. sinensis cinnamyl alcohol dehydrogenase (CsCAD1) catalyzes the formation of p-coumaryl alcohol participation in lignin synthesis. Our findings highlight the role of brassinolide-mediated lignin biosynthesis of the tea plant in response to T. aurantii feeding.PMID:39579374 | DOI:10.1021/acs.jafc.4c10093

J Agric Food Chem. 2024 Nov 23. doi: 10.1021/acs.jafc.4c07292. Online ahead of print.ABSTRACTCrabs marketed off-season in lunar June often have a brown hepatopancreas (BH) that tastes bitter, unlike the nonbitter orange hepatopancreas (OH). We conducted nontargeted and widely targeted metabolomics analyses on both raw and cooked orange and brown hepatopancreas of Eriocheir sinensis. A total of 115 bitter metabolites were identified, including oxylipins, amino acids, small peptides, nucleotides, vitamins, and coenzymes. Targeted quantitative analysis revealed that seven oxylipins were major contributors to the bitterness of BH. The primary metabolic pathways affecting hepatopancreas bitterness involved the production of unsaturated fatty acids and α-linolenic acid metabolism. Furthermore, specific odorants were produced from OH and BH groups during heat treatment, namely ethyl caproate and methional, respectively. Moreover, differential metabolites were found to act as odor precursors, resulting in a brown and bitter hepatopancreas with poor odor quality. This study elucidates the generation of bitter substances in the hepatopancreas of Eriocheir sinensis through metabolic pathways and thermal reaction pathways.PMID:39579135 | DOI:10.1021/acs.jafc.4c07292

Environ Sci Technol. 2024 Nov 23. doi: 10.1021/acs.est.4c06892. Online ahead of print.ABSTRACTEstrogens play a crucial role in regulating various biological responses during the early stages of neurodevelopment. Benzophenone-2 (BP2), a widely used organic ultraviolet (UV) filter, has been proven as an estrogenic compound, whereas the estrogenic effects of BP2 on neurodevelopment remain largely unknown. Here, we investigated the neurodevelopmental toxicity of BP2 by exposing zebrafish embryos from 2 to 120 h postfertilization (hpf) at environmentally relevant concentrations. We demonstrated that early life exposure to BP2 induced multiple concentration-dependent impairments in the nervous system, including hypoactivity, abnormal brain morphology, impaired neurocyte proliferation, shortened axon, and increased neurocyte apoptosis. Moreover, metabolomic profiling revealed a decrease in dopamine (DA) and its metabolites in BP2-treated larvae. Using E2 treatment and morpholino knockdown assays, we provided strong genetic evidence that the BP2-induced behavioral disorders were associated with estrogen-dependent signaling, especially estrogen receptors 2a and 2b (esr2). Subsequently, transcriptomic profiling indicated that the activation of esr2 further inhibited the expression of LIM homeobox transcription factor 1 β a (lmx1ba), which is vital for normal neurodevelopment. Consistently, the overexpression of lmx1ba and inhibition of esr2 obviously alleviated BP2-caused neurotoxicity, uncovering a seminal role of esr2 and lmx1ba in BP2-induced neurodevelopmental toxicity. Our findings provide the first evidence in fish that BP2 can induce neurodevelopmental deficits and brain dysfunction and offer novel insights into the mechanisms of toxicity of BP2 as well as other emerging benzophenones.PMID:39579127 | DOI:10.1021/acs.est.4c06892

J Appl Toxicol. 2024 Nov 23. doi: 10.1002/jat.4728. Online ahead of print.ABSTRACTErgothioneine (EGT) is a diet-derived natural sulfur-containing amino acid that exhibits strong anti-oxidant and anti-inflammation activities. Oxidative stress and chronic inflammatory injury are predominant pro-fibrogenic factors. Therefore, EGT may have therapeutic potential against liver fibrosis; however, its underlying mechanism is incompletely understood. This study aimed at investigating the protective effects of EGT on liver fibrosis based on metabonomics and network pharmacology. A mouse model of liver fibrosis was established by intraperitoneal injection with 40% CCl4 solution (2 mL/kg, twice a week) and intragastric administration with EGT (5, 10 mg/kg/d) for six weeks. Results showed that EGT improved liver function by reducing serum levels of ALT (alanine aminotransferase), AST (aspartate aminotransferase), and TBIL (total bilirubin), and alleviated liver fibrosis by reducing LN (laminin) and HyP (hydroxyproline) levels, decreasing expressions of α-SMA (α-smooth muscle actin), Col-I (collagen type I), and Col-III (collagen type III), and improving pathological changes. EGT also significantly inhibited CCl4-induced hepatic inflammation and TGF-β/Smads signaling pathway. Metabolomics identified six key metabolic pathways, such as purine metabolism, glycerophospholipid metabolism, and sphingolipid metabolism, and eight key metabolites, such as xanthine, guanine, ATP, phosphatidylcholine, and sphingosine. Network pharmacology analysis showed that IL-17, cAMP and NF-κB signaling pathways were potential key mechanisms. Integrated analysis revealed that PLA2G2A might be a potential target of EGT against liver fibrosis. EGT may inhibit the glycerophospholipid metabolism through PLA2G2A to inhibit the TGF-β/Smads signaling pathway, thereby alleviating fibrosis. The present study indicates that EGT may be considered a valid therapeutic strategy to regress liver fibrosis, and provides novel insights into the pharmacological mechanism of EGT against liver fibrosis.PMID:39579000 | DOI:10.1002/jat.4728

Microbiome. 2024 Nov 23;12(1):247. doi: 10.1186/s40168-024-01964-0.ABSTRACTBACKGROUND: Liver damage from nonalcoholic steatohepatitis (NASH) presents a significant challenge to the health and productivity of ruminants. However, the regulatory mechanisms behind variations in NASH susceptibility remain unclear. The gut‒liver axis, particularly the enterohepatic circulation of bile acids (BAs), plays a crucial role in regulating the liver diseases. Since the ileum is the primary site for BAs reabsorption and return to the liver, we analysed the ileal metagenome and metabolome, liver and serum metabolome, and liver single-nuclei transcriptome of NASH-resistant and susceptible goats together with a mice validation model to explore how ileal microbial BAs metabolism affects liver metabolism and immunity, uncovering the key mechanisms behind varied NASH pathogenesis in dairy goats.RESULTS: In NASH goats, increased total cholesterol (TC), triglyceride (TG), and primary BAs and decreased secondary BAs in the liver and serum promoted hepatic fat accumulation. Increased ileal Escherichia coli, Erysipelotrichaceae bacterium and Streptococcus pneumoniae as well as proinflammatory compounds damaged ileal histological morphology, and increased ileal permeability contributes to liver inflammation. In NASH-tolerance (NASH-T) goats, increased ursodeoxycholic acid (UDCA), isodeoxycholic acid (isoDCA) and isolithocholic acid (isoLCA) in the liver, serum and ileal contents were attributed to ileal secondary BAs-producing bacteria (Clostridium, Bifidobacterium and Lactobacillus) and key microbial genes encoding enzymes. Meanwhile, decreased T-helper 17 (TH17) cells and increased regulatory T (Treg) cells proportion were identified in both liver and ileum of NASH-T goats. To further validate whether these key BAs affected the progression of NASH by regulating the proliferation of TH17 and Treg cells, the oral administration of bacterial UDCA, isoDCA and isoLCA to a high-fat diet-induced NASH mouse model confirmed the amelioration of NASH through the TH17 cell differentiation/IL-17 signalling/PPAR signalling pathway by these bacterial secondary BAs.CONCLUSION: This study revealed the roles of ileal microbiome and its secondary BAs in resilience and susceptibility to NASH by affecting the hepatic Treg and TH17 cells proportion in dairy goats. Bacterial UDCA, isoDCA and isoLCA were demonstrated to alleviate NASH and could be novel postbiotics to modulate and improve the liver health in ruminants. Video Abstract.PMID:39578870 | DOI:10.1186/s40168-024-01964-0

BMC Plant Biol. 2024 Nov 22;24(1):1112. doi: 10.1186/s12870-024-05825-8.ABSTRACTBamboo, as a timber plant, holds significant environmental and economic value. Dendrocalamus farinosus is particularly valuable as it serves both as a source of bamboo shoots and timber, offering high yield, strong disease resistance, and superior fiber quality. Our previous study demonstrated that bio-organic fertilizers promoted the growth of D. farinosus and significantly altered the cellulose and lignin content, key components of the secondary cell wall in culms. However, the underlying regulatory mechanisms remain unclear. In this study, we used metabolomic and transcriptomic analyses to uncover the potential mechanisms by which bio-organic fertilizers affect the secondary cell wall biosynthesis in D. farinosus. A total of 1,437 metabolites were identified, with 20 differential metabolites significantly enriched in the phenylpropanoid metabolic pathway in bamboo shoots (7 upregulated; 13 downregulated). We identified 8,075 differentially expressed genes in bamboo shoots, including 72 genes potentially involved in lignin and flavonoid biosynthesis (6 upregulated; 66 downregulated). In internodes, we identified 5,324 differentially expressed genes, including 83 genes potentially involved in secondary cell wall biosynthesis (43 upregulated; 39 downregulated). Quantitative real-time PCR (qRT-PCR) validated the expression patterns of 8 key genes in internodes. The results suggest that bio-organic fertilizers may affect secondary cell wall biosynthesis in internodes by inhibiting the phenylpropanoid metabolic pathway in D. farinosus shoots. Our study offers insights into the efficient utilization of bamboo and lignocellulosic biomass, serving as a valuable resource for future research.PMID:39578723 | DOI:10.1186/s12870-024-05825-8

Nat Metab. 2024 Nov 22. doi: 10.1038/s42255-024-01170-0. Online ahead of print.ABSTRACTCushing's syndrome is caused by an elevation of endogenous or pharmacologically administered glucocorticoids. Acyl coenzyme A binding protein (ACBP, encoded by the gene diazepam binding inhibitor, Dbi) stimulates food intake and lipo-anabolic reactions. Here we found that plasma ACBP/DBI concentrations were elevated in patients and mice with Cushing's syndrome. We used several methods for ACBP/DBI inhibition in mice, namely, (1) induction of ACBP/DBI autoantibodies, (2) injection of a neutralizing monoclonal antibody, (3) body-wide or hepatocyte-specific knockout of the Dbi gene, (4) mutation of the ACBP/DBI receptor Gabrg2 and (5) injections of triiodothyronine or (6) the thyroid hormone receptor-β agonist resmetirom to block Dbi transcription. These six approaches abolished manifestations of Cushing's syndrome such as increased food intake, weight gain, excessive adiposity, liver damage, hypertriglyceridaemia and type 2 diabetes. In conclusion, it appears that ACBP/DBI constitutes an actionable target that is causally involved in the development of Cushing's syndrome.PMID:39578649 | DOI:10.1038/s42255-024-01170-0

Nat Microbiol. 2024 Nov 22. doi: 10.1038/s41564-024-01863-y. Online ahead of print.NO ABSTRACTPMID:39578576 | DOI:10.1038/s41564-024-01863-y

Sci Rep. 2024 Nov 22;14(1):28972. doi: 10.1038/s41598-024-80550-8.ABSTRACTSepsis, characterized as a systemic inflammatory response triggered by the invasion of pathogens, represents a continuum that may escalate from mild systemic infection to severe sepsis, potentially resulting in septic shock and multiple organ dysfunction syndrome. Advancements in lipidomics and metabolomics have unveiled the complex role of fatty acid metabolism (FAM) in both healthy and pathological states. Leveraging bioinformatics, this investigation aimed to identify and substantiate potential FAM-related genes (FAMGs) implicated in sepsis. The approach encompassed a differential expression analysis across a pool of 36 candidate FAMGs. GSEA and GSVA were employed to assess the biological significance and pathways associated with these genes. Furthermore, Lasso regression and SVM-RFE methodologies were implemented to determine key hub genes and assess the diagnostic prowess of nine selected FAMGs in sepsis identification. The study also investigated the correlation between these hub FAMGs. Validation was conducted through expression-level analysis using the GSE13904 and GSE65682 datasets. The study identified 13 sepsis-associated FAMGs, including ABCD2, ACSL3, ACSM1, ACSS1, ACSS2, ACOX1, ALDH9A1, ACACA, ACACB, FASN, OLAH, PPT1, and ELOVL4. As demonstrated by functional enrichment analysis results, these genes played key roles in several critical biological pathways, such as the Peroxisome, PPAR signaling pathway, and Insulin signaling pathway, all of which are intricately linked to metabolic regulation and inflammatory responses. The diagnostic potential of these FAMGs was further highlighted. In short, the expression patterns of these FAMGs c effectively distinguished sepsis cases from non-septic controls, which suggested that they may be promising biomarkers for early sepsis detection. This discovery not only enhanced our understanding of the molecular mechanisms underpinning sepsis but also paved the way for developing novel diagnostic tools and therapeutic strategies targeting metabolic dysregulation in septic patients. This research sheds light on 13 FAMGs associated with sepsis, providing valuable insights into novel biomarkers for this condition and facilitating the monitoring of its progression. These findings underscore the significance of purine metabolism in sepsis pathogenesis and open avenues for further investigation into therapeutic targets.PMID:39578562 | DOI:10.1038/s41598-024-80550-8

Sci Rep. 2024 Nov 22;14(1):28943. doi: 10.1038/s41598-024-80616-7.ABSTRACTLiver fibrosis is a common progressive liver disease that can cause liver dysfunction and lead to serious complications. Zi Qi decoction (ZQ) is a traditional formulation that exerts pharmacological effects on the treatment of liver fibrosis. However, precise intervention mechanisms remain unclear. The aim of this study was to synergistically harness proteomics and metabolomics techniques to elucidate the specific target of ZQ and its potential mechanism of action. A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was established. Subsequently, the protective effect of ZQ on liver fibrosis mice was evaluated according to histopathological examination and biochemical indicators. Quantitative proteomics based on data independent acquisition (DIA) and non-targeted metabolomic analyses revealed the pharmacodynamic mechanism of ZQ. In addition, various cellular and molecular assays were used to detect changes in glycolysis levels in LSECs and mouse liver fibrosis models. The study results showed that ZQ significantly alleviated CCl4-induced liver injury and fibrosis in mice. DIA-based quantitative proteomics and non-targeted metabolomics analyses indicated that ZQ treatment downregulated glycolysis-related proteins such as PKM2, PFKP, and HK2, while regulating glycolysis-related metabolites and pathways. In addition, ZQ down-regulated glycolytic activity in mice with liver fibrosis and in LSECs, and inhibited CXCL1 secretion and neutrophil recruitment. ZQ inhibited LSEC glycolysis and mitigated neutrophil infiltration, thereby playing a therapeutic role in liver fibrosis.PMID:39578538 | DOI:10.1038/s41598-024-80616-7

Sci Rep. 2024 Nov 22;14(1):28993. doi: 10.1038/s41598-024-79229-x.ABSTRACTCyclooxygenase (COX) and lipoxygenase (LOX) enzymes play a pivotal role in producing pro-inflammatory eicosanoids, including prostaglandins (PGs) and leukotrienes (LTs), in the inflammation process. Mitragynine is a primary alkaloid contained in the kratom's leaves and has been reported to show anti-inflammatory activity by suppressing COX-2 mRNA translation to lowering PGs synthesis. In this study, the Kratom's alkaloid extract containing ~ 46% mitragynine was found to exhibit dual inhibition activity towards COX-2/5-LOX enzymes at concentrations below 25 ppm in the LPS-induced RAW 264.7 macrophage cells. At these levels, no cell toxicity was observed while the cells became death (e.g., 10-46% viability at 50-100 ppm) and only COX-2 inhibition activity was observed after exposed with more than 25 ppm of alkaloid extract. In contrast, the methanolic-crude extract of Kratom's leaf containing ~ 5% mitragynine showed no inhibition toward COX-2/5-LOX enzymes and did not toxic onto the cells, even after treated at 100 ppm. The alkaloid extract suppressed several antiinflammation parameters, including ROS (64% reduction at 25 ppm), NO (30% reduction at 25 ppm), TNF-α (~ 50% reduction at 25 ppm), and IL-6 production (60% reduction at 6.25 ppm). In silico molecular studies indicated strong binding affinity of Kratom alkaloids to COX-2 and 5-LOX active sites, supporting the Kratom's alkaloids to have great potential dual inhibition activity towards COX-2/5-LOX enzymes and to be developed as a safer NSAIDs with fewer side effects.PMID:39578527 | DOI:10.1038/s41598-024-79229-x