PubMed

Chemosphere. 2024 Aug 30:143229. doi: 10.1016/j.chemosphere.2024.143229. Online ahead of print.ABSTRACTDi(2-ethylhexyl)phthalate (DEHP) is one of the most widely used plasticizers in plastic manufacturing. However, the toxicological effects of DEHP on dandelions remain poorly understood. This study comprehensively analyzed and explored the response mechanisms of dandelions to 1, 10, 50, and 100 mg L-1 DEHP influencing the morphophysiological growth, metabolomics, and molecular docking. DEHP reduced chlorophyll synthesis, inhibited plant growth, and induced oxidative-state-associated stress, which was manifested by the excessive production of reactive oxygen species, an increase in antioxidant enzyme activities, and enhanced synthesis of some osmoregulatory compounds, including proline and soluble protein. An analysis of the integrated biological response index showed that the toxicity was dose-dependent. Molecular docking demonstrated that DEHP could bind stably to three enzymes, and the binding energy was peroxidase (POD) > catalase (CAT) > superoxide dismutase (SOD). Metabolomics revealed that metabolite abundance and metabolic pathways were altered by DEHP, with 88 and 72 primary metabolites identified in shoots and roots, respectively. Amino acid, sugar, and organic acid metabolism were severely disturbed, with the most significant effects being on carbohydrate metabolism, valine, leucine, and isoleucine biosynthesis. Our study elucidated the influence of DEHP exposure on dandelions, providing new insights into the toxicity mechanisms and toxicological risk assessment.PMID:39218265 | DOI:10.1016/j.chemosphere.2024.143229

Sci Total Environ. 2024 Aug 30:175931. doi: 10.1016/j.scitotenv.2024.175931. Online ahead of print.ABSTRACTMonocrotaline (MCT) is a toxic pyrrolizidine alkaloid found in plants of the Crotalaria genus. As primary pollinators of Crotalaria plants, honeybees come into contact with this harmful substance. However, limited research has been conducted on the effects of MCT on Apis mellifera, particularly the risks of long-term exposure to sublethal concentrations. Through evaluating the proboscis extension reflex (PER) ability, analyzing the honeybee brain transcriptome, and analyzing the honeybee hemolymph metabolome, we discovered that sublethal concentrations of MCT impair the olfactory and memory capabilities of honeybees by affecting tryptophan (Trp) metabolism. Furthermore, MCT upregulates the expression of the corazonin receptor (CrzR) gene in the honeybee brain, which elevates reactive oxygen species (ROS) levels in the brain while reducing glucose levels in the hemolymph, consequently shortening the honeybees' lifespan. Our findings regarding the multifaceted impact of MCT on honeybees lay the foundation for exploring its toxicological pathways and management in honeybee populations.PMID:39218096 | DOI:10.1016/j.scitotenv.2024.175931

Biochem Biophys Res Commun. 2024 Aug 29;734:150621. doi: 10.1016/j.bbrc.2024.150621. Online ahead of print.ABSTRACTEpigenetic modifications and their alterations can cause variation in gene expression patterns which can ultimately affect a healthy individual. Until a few years ago, it was thought that the epigenome affects the transcriptome which can regulate the proteome and the metabolome. Recent studies have shown that the metabolome independently also plays a major role in regulating the epigenome bypassing the need for transcriptomic control. Alternatively, an imbalanced metabolome, stemming from transcriptome abnormalities, can further impact the transcriptome, creating a self-perpetuating cycle of interconnected occurrences. As a result, external factors such as nutrient intake and diet can have a direct impact on the metabolic pools and its reprogramming can change the levels and activity of epigenetic modifiers. Thus, the epigenetic landscape steers toward a diseased condition. In this review, we have discussed how different metabolites and dietary patterns can bring about changes in different arms of the epigenetic machinery such as methylation, acetylation as well as RNA mediated epigenetic mechanisms. We checked for limiting metabolites such as αKG, acetyl-CoA, ATP, NAD+, and FAD, whose abundance levels can lead to common diseases such as cancer, neurodegeneration etc. This gives a clearer picture of how an integrated approach including both epigenetics and metabolomics can be used for therapeutic purposes.PMID:39217811 | DOI:10.1016/j.bbrc.2024.150621

J Pharm Biomed Anal. 2024 Aug 22;251:116443. doi: 10.1016/j.jpba.2024.116443. Online ahead of print.ABSTRACTAccurate and objective estimation of the postmortem interval (PMI) is crucial in forensic practice. This study aimed to infer PMI through equations based on the relationship between PMI and metabolomics biomarkers.Rats were subjected to models representing various temperatures and causes of death, with blood collected at different intervals. Untargeted gas chromatographymass spectrometry metabolomics detection methods were developed, and candidate biomarkers were chosen as co-differentially expressed metabolites in four models. A targeted method was then developed for quantitatively determining candidate biomarkers. Animal tests and human cadaver samples with clearly documented causes of death and time were used to verify the reliability of the regression equation.Results: Unique differential metabolites for CO poisoning deaths included 2,3-butanediol, hypoxanthine, and dehydrated hexanol, while those for mechanical asphyxia deaths comprised propylamine, 1,3-propylene glycol, phosphoric acid, and sorbitol. Pyruvate, glycerol and isoleucine were identified as candidate biomarkers. Human case results demonstrated the method's potential (error rate < 20 %). The findings of this study may offer reference points for estimating PMI and causes of death in forensic practice.PMID:39217704 | DOI:10.1016/j.jpba.2024.116443

Phytomedicine. 2024 Aug 23;134:155968. doi: 10.1016/j.phymed.2024.155968. Online ahead of print.ABSTRACTBACKGROUND: The incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing globally and more so in China. The characteristics of liver-mediated metabolites and related key enzymes are rarely reported in HTG-AP. Chaiqin chengqi decoction (CQCQD) has been shown to protect against AP including HTG-AP in both patients and rodent models, but the underlying mechanisms in HTG-AP remain unexplored.PURPOSE: To assess the characteristics of liver-mediated metabolism and the therapeutic mechanisms of CQCQD in HTG-AP.METHODS: Male human apolipoprotein C3 transgenic (hApoC3-Tg; leading to HTG) mice or wild-type littermates received 7 intraperitoneal injections of cerulein (100 μg/kg) to establish HTG-AP and CER-AP, respectively. In HTG-AP, some mice received CQCQD (5.5 g/kg) gavage at 1, 5 or 9 h after disease induction. AP severity and related liver injury were determined by serological and histological parameters; and underlying mechanisms were identified by lipidomics and molecular biology. Molecular docking was used to identify key interactions between CQCQD compounds and metabolic enzymes, and subsequently validated in vitro in hepatocytes.RESULTS: HTG-AP was associated with increased disease severity indices including augmented liver injury compared to CER-AP. CQCQD treatment reduced severity and liver injury of HTG-AP. Glycerophospholipid (GPL) metabolism was the most disturbed pathway in HTG-AP in comparison to HTG alone. In HTG-AP, the mRNA level of GPL enzymes involved in phosphocholine (PC) and phosphatidylethanolamine (PE) synthesis (Pcyt1a, Pcyt2, Pemt, and Lpcat) were markedly upregulated in the liver. Of the GPL metabolites, lysophosphatidylethanolamine LPE(16:0) in serum of HTG-AP was significantly elevated and positively correlated with the pancreas histopathology score (r = 0.65). In vitro, supernatant from Pcyt2-overexpressing hepatocytes co-incubated with LPE(16:0) or phospholipase A2 (a PC- and PE-hydrolyzing enzyme) alone induced pancreatic acinar cell death. CQCQD treatment downregulated PCYT1a and PCYT2 enzyme levels in the liver. Hesperidin and narirutin were identified top two CQCQD compounds with highest affinity docking to PCYT1a and PCYT2. Both hesperidin and narirutin reduced the level of some GPL metabolites in hepatocytes.CONCLUSION: Liver-mediated GPL metabolism is excessively activated in HTG-AP with serum LPE(16:0) level correlating with disease severity. CQCQD reduces HTG-AP severity partially via modulating key enzymes in GPL metabolism pathway.PMID:39217651 | DOI:10.1016/j.phymed.2024.155968

Water Res. 2024 Aug 30;266:122351. doi: 10.1016/j.watres.2024.122351. Online ahead of print.ABSTRACTIn this study, the transformation mechanisms of extracellular polymeric substances (EPS) during ultraviolet/peracetic acid (UV/PAA) disinfection were elucidated based on multiple molecular-level analyses. After UV/PAA disinfection, the contents of soluble EPS (S-EPS), loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS) were reduced by 70.47 %, 57.05 % and 47.46 %, respectively. Fluorescence excitation-emission matrix-parallel factor and Fourier transform ion cyclotron resonance mass spectrometry analyses showed that during UV/PAA disinfection, EPS was transformed from the state characterized by high aromaticity, low saturation and low oxidation to the one with reduced aromaticity, increased saturation and higher oxidation. Specifically, sulfur-containing molecules (CHOS, CHONS, etc.) in EPS were converted into highly saturated and oxidized species (such as CHO), with the aromaticity index (AImod) decreasing by up to 53.84 %. Molecular characteristics analyses further indicated that saturation degree, oxidation state of carbon and molecular weight exhibited the most significant changes in S-EPS, LB-EPS and TB-EPS, respectively. Additionally, mechanistic analysis revealed that oxygen addition reaction was the predominant reaction for S-EPS (+O) and TB-EPS (+3O) (accounting for 31.78 % and 36.47 %, respectively), while the dealkylation was the main reaction for LB-EPS (29.73 %). The results were consistent with functional groups sequential responses analyzed by Fourier transform infrared and two-dimensional correlation spectroscopy, and were further verified by density functional theory calculations. Most reactions were thermodynamically feasible, with reaction sites predominantly located at functional groups such as CO, CO, CN and aromatic rings. Moreover, metabolomics analysis suggested that changes in metabolites in raw secondary effluent during UV/PAA disinfection were strongly correlated with EPS transformation. Our study not only provides a strong basis for understanding EPS transformation during UV/PAA disinfection at molecular-level but also offers valuable insights for the application this promising disinfection process.PMID:39217641 | DOI:10.1016/j.watres.2024.122351

Eur J Med Res. 2024 Aug 31;29(1):446. doi: 10.1186/s40001-024-02014-z.ABSTRACTBACKGROUND: Aortic stenosis (AS) is a prevalent and serious valvular heart disease with a complex etiology involving genetic predispositions, lipid dysregulation, and inflammation. The specific roles of lipid and protein biomarkers in AS development are not fully elucidated. This study aimed to elucidate the causal relationships between lipidome, inflammatory proteins, and AS using Mendelian randomization (MR), identifying potential therapeutic targets.METHODS: Utilizing data from large-scale genome-wide association studies (GWAS) and genome-wide protein quantitative trait loci (pQTL) studies, we conducted MR analyses on 179 plasma lipidome and 91 inflammatory proteins to assess their causal associations with AS. Our approach included Inverse Variance Weighting (IVW), Wald ratio, and robust adjusted profile score (RAPS) analyses to refine these associations. MR-Egger regression was used to address directional horizontal pleiotropy.RESULTS: Our MR analysis showed that genetically predicted 50 lipids were associated with AS, including 38 as risk factors [(9 Sterol ester, 18 Phosphatidylcholine, 4 Phosphatidylethanolamine, 1 Phosphatidylinositol and 6 Triacylglycerol)] and 12 as protective. Sterol ester (27:1/17:1) emerged as the most significant risk factor with an odds ratio (OR) of 3.11. Additionally, two inflammatory proteins, fibroblast growth factor 19 (FGF19) (OR = 0.830, P = 0.015), and interleukin 6 (IL-6) (OR = 0.729, P = 1.79E-04) were significantly associated with reduced AS risk. However, a two-step MR analysis showed no significant mediated correlations between these proteins and the lipid-AS pathway.CONCLUSION: This study reveals complex lipid and protein interactions in AS, identifying potential molecular targets for therapy. These results go beyond traditional lipid profiling and significantly advance our genetic and molecular understanding of AS, highlighting potential pathways for intervention and prevention.PMID:39217396 | DOI:10.1186/s40001-024-02014-z

Metabolism. 2024 Aug 29:156015. doi: 10.1016/j.metabol.2024.156015. Online ahead of print.ABSTRACTThe prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, making it the leading etiology of chronic liver diseases and a prime cause of liver-related mortality. MASLD can progress into steatohepatitis (termed MASH), fibrosis, cirrhosis, and ultimately cancer. MASLD is associated with increased risks of hepatocellular carcinoma (HCC) and also extrahepatic malignancies, which can develop in both cirrhotic and non-cirrhotic patients, emphasizing the importance of identifying patients with MASLD at risk of developing MASLD-associated malignancies. However, the optimal screening, diagnostic, and risk stratification strategies for patients with MASLD at risk of cancer are still under debate. Individuals with MASH-associated cirrhosis are recommended to undergo surveillance for HCC (e.g. by ultrasound and biomarkers) every six months. No specific screening approaches for MASLD-related malignancies in non-cirrhotic cases are established to date. The rapidly developing omics technologies, including genetics, metabolomics, and proteomics, show great potential for discovering non-invasive markers to fulfill this unmet need. This review provides an overview on the incidence and mortality of MASLD-associated malignancies, current strategies for HCC screening, surveillance and diagnosis in patients with MASLD, and the evolving role of omics technologies in the discovery of non-invasive markers for the prediction and risk stratification of MASLD-associated HCC. SUMMARY.PMID:39216799 | DOI:10.1016/j.metabol.2024.156015

J Ethnopharmacol. 2024 Aug 29:118765. doi: 10.1016/j.jep.2024.118765. Online ahead of print.NO ABSTRACTPMID:39216774 | DOI:10.1016/j.jep.2024.118765

J Ethnopharmacol. 2024 Aug 29:118763. doi: 10.1016/j.jep.2024.118763. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: At present,the global form of hypertension is severe,and liver-yang-hyperactivity hypertension（GYSK hypertension）is the most common type of hypertension.Folium Polygoni Cuspidati（HZY）are mainly used in Yunnan,China,to treat dizziness,headache,and hypertension caused by GYSK,and the content of the active ingredients of HZY and its efficacy varies in different periods.However,the mechanism of action and the effect of harvesting period are not clear.AIM OF THE STUDY: The purpose of this research was to investigate the effect of HZY in April and September on GYSK hypertension.MATERIALS AND METHODS: The model of GYSK hypertension was established with aconite decoction and L-NAME,and the blood pressure,the symptoms of GYSK,the cardiac index and the pathological changes of aorta were observed,to study the effect of HZY in April and September on GYSK hypertension.The chemical composition of HZY was analysed by UPLC-QTOF-MS and its mechanism for the treatment of GYSK hypertension was predicted by network pharmacological studies and experimentally validated using serum metabolomics and western blot techniques.RESULTS: April HZY and September HZY can significantly improve the GYSK symptoms of rats,inhibit the RAAS system,improve oxidative stress and regulate blood lipids so as to play a blood pressure lowering efficacy and have a protective effect on the vascular endothelial cells.UPLC-QTOF-MS yielded 29 components of HZY,and network pharmacology predicted that its mechanism may be related to Lipid and atherosclerosis,PI3K/Akt signaling pathway,MAPK signaling pathway and TNF signaling pathway,etc.Western Blot validation showed that HZY activated PI3K,p-Akt protein expression and inhibited p-erk,p-p38 and TNF-α protein expression.Serum metabolomics suggested that April HZY exerts its efficacy mainly by regulating amino acid metabolism and September HZY mainly by regulating lipid metabolism.CONCLUSIONS: In GYSK hypertensive rats treated for three weeks,both April HZY and September HZY could have antihypertensive effects,but the mechanisms of action were different and similar,both could regulate metabolite disorders of sugars,lipids,aminoacids and peptides,and regulate blood pressure through the PI3K/Akt-eNOS and MAPK signalling pathways,with the difference that April HZY had stronger regulatory effects on the metabolism of amino acids.metabolism.PMID:39216773 | DOI:10.1016/j.jep.2024.118763

Environ Pollut. 2024 Aug 29:124865. doi: 10.1016/j.envpol.2024.124865. Online ahead of print.ABSTRACTPer- and polyfluoroalkyl substances (PFAS) have been linked to kidney function. Studies have shown that PFAS can cause changes in lipid metabolism and that lipids play an important role in regulating kidney function. However, few studies have explored the overall impact of PFAS mixture on kidney function. Moreover, the mechanisms by which PFAS influences kidney function remain unclear. This study was performed to investigate the overall impact of PFAS mixture on kidney function indexes, dissect the mechanism by which PFAS affect kidney function by analyzing lipid molecule profiles, and analyze the associations between different subclasses of lipids and kidney function indexes. We measured blood PFAS levels and kidney function indexes in a community population containing 278 males. Metabolomic analysis detected 332 lipid molecules. A quantile-based g-computation model was applied to assess the overall effect of PFAS mixture on kidney function index, and revealed that PFAS mixture were associated with a higher level of uric acid (UA). Linear regression analysis demonstrated a positive association between PFOA and UA, and logistic regression analysis indicated a positive association between PFOA and hyperuricemia odds. Notably, none of the PFAS were associated with the estimated glomerular filtration rate, indicating that PFAS didn't have an obvious effect on glomerular filtration. Further analysis identified 20 lipid molecules associated with both PFOA and UA. High-dimensional mediation effect analysis showed that seven lipid molecules (one glycerophospholipids, three fatty acyls and three prenol lipids) mediated the association between PFOA and UA. Additionally, quantile-based g-computation analysis revealed positive associations between specific lipid subclasses-mainly fatty acid esters, fatty acids and conjugates, and sesquiterpenoids-and kidney function indexes. Our findings provide insights into the renal toxicity of PFAS and may also lead to more in-depth investigations using animal models and other population studies.PMID:39216665 | DOI:10.1016/j.envpol.2024.124865

Int J Food Microbiol. 2024 Aug 28;425:110891. doi: 10.1016/j.ijfoodmicro.2024.110891. Online ahead of print.ABSTRACTAlthough cold storage at 4 °C can effectively prolong the shelf life of raw milk, it cannot prevent its eventual spoilage. In this study, we analyzed the main physicochemical and microbial indexes of raw milk stored at 4 °C for 6 days. The changes in microbial profiles and milk metabolites and their relationship during refrigeration were also explored. Metagenomic analysis performed using the Illumina Hiseq Xten sequencing platform revealed that the dominant genera in raw milk evolved from Acinetobacter, Streptococcus, Staphylococcus, and Anaplasma to Flavobacterium, Pseudomonas, and Lactococcus during cold storage. Using the UHPLC-Q-TOF MS method, 77 significantly different metabolites (p < 0.05) were identified, among which lipids were the most abundant (37). The most significant metabolic changes largely occurred at 3-4 days of refrigeration, coinciding with the rapid increase in dominant psychrotrophic bacteria. Subsequently, correlation analysis demonstrated that these lipid-related metabolites were significantly associated with Acinetobacter, Flavobacterium, and Pseudomonas. Both macro indicators and microanalysis indicated that the key stage of quality changes in raw milk was 3-4 days. Thus, this stage can be targeted for the quality control of raw milk.PMID:39216362 | DOI:10.1016/j.ijfoodmicro.2024.110891

Phytomedicine. 2024 Aug 26;134:155992. doi: 10.1016/j.phymed.2024.155992. Online ahead of print.ABSTRACTBACKGROUND: Polygoni Cuspidati Rhizoma et Radix (Huzhang in Chinese), refers to the root and rhizome of Polygonum cuspidatum Sieb. et Zucc. Huzhang is commonly used in clinical practice for the prevention and treatment of diabetes and its complications, but its active components and regulatory mechanisms have not yet been thoroughly analyzed.PURPOSE: The network pharmacology combined with multi-omics analysis will be employed to dissect the substance basis and action mechanism of Huzhang in exerting its anti-diabetic activity.METHODS: This study employed phenotypic indicators for baseline assessment, followed by integrated analysis using network pharmacology, metabolomics, transcriptomics, and qPCR technology to elucidate the active components and pharmacological mechanisms of Huzhang.RESULTS: The analysis of network pharmacology revealed that polydatin is a potential active component responsible for the anti-T2DM pharmacological effects of Huzhang. In vivo experimental results demonstrated that polydatin significantly regulates blood glucose, lipid levels, liver function, and liver pathological damage in diabetic rats. Analysis results from transcriptomics, metabolomics, and qPCR validation showed that polydatin comprehensively regulates glucose and lipid metabolism in T2DM by modulating bile acid metabolism, fatty acid oxidation, and lipogenesis.CONCLUSION: Polydatin is a key component of Huzhang in treating T2DM, and its regulatory mechanisms are diverse, indicating significant development potential.PMID:39216300 | DOI:10.1016/j.phymed.2024.155992

J Chromatogr A. 2024 Aug 27;1734:465317. doi: 10.1016/j.chroma.2024.465317. Online ahead of print.ABSTRACTAristolochic acids are one of the major compounds in aristolochia plants, which are nephrotoxic and carcinogenic. A method was established for the detection and identification of aristolochic acids and their DNA adducts in four different herbs using ultra-high performance liquid chromatography-ion mobility quadrupole time-of flight mass spectrometry. Solid phase extraction conditions were optimized to improve the sensitivity of the experiment by using 40 mg of C18 as adsorbent and 100 μL ethanol as elution solvent. At a collision energy of 10-40 eV, these compounds and cleavage patterns were precisely identified and analyzed by secondary fragmentation and collision cross section values. The obtained mass spectrometry data were then analyzed by targeted metabolomics, including principal component analysis, partial least squares-discriminant analysis and hierarchical clustering analysis, and importing the samples in the established model, the confidence values can reach 0.61 and 0.76. All in all, this method can provide a useful tool for the detection of aristolochic acids and deoxyribonucleic acid adducts. In conclusion, this method was successfully used for the detection and identification of aristolochic acids and their DNA adducts.PMID:39216282 | DOI:10.1016/j.chroma.2024.465317

Ecotoxicol Environ Saf. 2024 Aug 30;283:116975. doi: 10.1016/j.ecoenv.2024.116975. Online ahead of print.ABSTRACTThe contribution of plant hormones and energy-rich compounds and their metabolites (ECMs) in alleviating aluminum (Al) toxicity by elevated pH remains to be clarified. For the first time, a targeted metabolome was applied to identify Al-pH-interaction-responsive hormones and ECMs in Citrus sinensis leaves. More Al-toxicity-responsive hormones and ECMs were identified at pH 4.0 [4 (10) upregulated and 7 (17) downregulated hormones (ECMs)] than those at pH 3.0 [1 (9) upregulated and 4 (14) downregulated hormones (ECMs)], suggesting that the elevated pH improved the adaptation of hormones and ECMs to Al toxicity in leaves. The roles of hormones and ECMs in reducing leaf Al toxicity mediated by elevated pH might include the following aspects: (a) improved leaf growth by upregulating the levels of jasmonoyl-L-isoleucine (JA-ILE), 6-benzyladenosine (BAPR), N6-isopentenyladenosine (IPR), cis-zeatin-O-glucoside riboside (cZROG), and auxins (AUXs), preventing Al toxicity-induced reduction of gibberellin (GA) biosynthesis, and avoiding jasmonic acid (JA)-mediated defense; (b) enhanced biosynthesis and accumulation of tryptophan (TRP), as well as the resulting increase in biosynthesis of auxin, melatonin and secondary metabolites (SMs); (c) improved ability to maintain the homeostasis of ATP and other phosphorus (P)-containing ECMs; and (d) enhanced internal detoxification of Al due to increased organic acid (OA) and SM accumulation and elevated ability to detoxify reactive oxygen species (ROS) due to enhanced SM accumulation. To conclude, the current results corroborate the hypotheses that elevated pH reduces Al toxicity by upregulating the ability to maintain the homeostasis of ATP and other P-containing ECMs in leaves under Al toxicity and (b) hormones participate in the elevated pH-mediated alleviation of Al toxicity by positively regulating growth, the ability to detoxify ROS, and the internal detoxification of Al in leaves under Al toxicity. Our findings provide novel insights into the roles of hormones and ECMs in mitigating Al toxicity mediated by the elevated pH.PMID:39216222 | DOI:10.1016/j.ecoenv.2024.116975

Ecotoxicol Environ Saf. 2024 Aug 30;283:116969. doi: 10.1016/j.ecoenv.2024.116969. Online ahead of print.ABSTRACTNovel Psychoactive Substances (NPS) derived from tryptamines has been detected in aquatic environments, leading to environmental toxicology concerns. However, the specific toxicological mechanism, underlying these NPS, remains unclear. In our previous work, we used 5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT) as the representative drug for NPS, and found that, 5-MeO-MiPT led to obvious behavioral inhibition and oxidative stress responses in zebrafishes model. In this study, Zebrafish were injected with varying concentrations of 5-MeO-MiPT for 30 days. RNA-seq, qPCR, metabolomics, and histopathological analyses were conducted to assess gene expression and tissue integrity. This study confirms that 5-MeO-MiPT substantially influences the transcription and expression of 13 selected genes, including ucp1, pet100, grik3, and grik4, mediated by the Gαq/11-PLCβ signaling pathway. We elucidate the molecular mechanism that 5-MeO-MiPT can inhibit DAG-Ca2+/Pkc/Erk, Pkc/Pla2/PLCs and Ca2+/Camk Ⅱ/NMDA, while enhance Ca2+/Creb. Those secondary signaling pathways may be the mechanisms mediating 5-MeO-MiPT inhibiting normal behavior in zebrafish. These findings offer novel insights into the toxicological effects and addiction mechanisms of 5-MeO-MiPT. Moreover, it presents promising avenues for investigating other tryptamine-based NPS and offers a new direction for diagnosing and treating liver-brain pathway-related diseases.PMID:39216220 | DOI:10.1016/j.ecoenv.2024.116969

Water Res. 2024 Aug 27;266:122347. doi: 10.1016/j.watres.2024.122347. Online ahead of print.ABSTRACTPhytoremediation is an effective solution to treat pollution with antibiotic compounds in aquatic environments; however, the underlying mechanisms for plants to cope with antibiotic pollutants are obscure. Here we used cell suspension culture to investigate the distribution and transformation of ciprofloxacin (CIP) in common reed (Phragmites australis) plants, as well as the accompanying phenotypic and metabolic responses of plants. By means of radioactive isotope labelling, we found that in total 68 % of CIP was transformed via intracellular Phase I transformation (reduction and methylation), Phase Ⅱ conjugation (glycosylation), and Phase Ⅲ compartmentalization (cell-bound residue formation mainly in cell walls, 23 %). The reduction and glycosylation products were secreted by the cells. To mitigate stress induced by CIP and its transformation products, the cells activated the defense system by up-regulating both intra- and extra-cellular antioxidant metabolites (e.g., catechin, l-cystine, and dehydroascorbic acid), anti-C/N metabolism disorder metabolites (e.g., succinic acid), secreting signaling (e.g., nicotinic acid), and anti-stress (e.g., allantoin) metabolites. Notably, the metabolic reprogramming could be involved in the CIP transformation process (e.g., glycosylation). Our findings reveal the strategy of wetland plants to cope with the stress from CIP by transforming the xenobiotic compound and reprogramming metabolism, and provide novel insights into the fate of antibiotics and plant defense mechanisms during phytoremediation.PMID:39216127 | DOI:10.1016/j.watres.2024.122347

Int Immunopharmacol. 2024 Aug 30;142(Pt A):113039. doi: 10.1016/j.intimp.2024.113039. Online ahead of print.ABSTRACTUlcerative colitis (UC) poses a threat to human health. The present study attempts to unravel the efficacy and potential mechanisms of paeoniflorin (PF), a naturally sourced active ingredient, for the management of UC. By establishing a DSS (dextran sulphate sodium)-induced experimental rat model of UC, this study found that PF was effective in ameliorating UC symptoms, inhibiting oxidative stress, inflammation and apoptosis, and repairing colonic epithelial damage. In addition, metabolomics revealed that PF may alleviate UC by primarily improving linoleic acid metabolism. Mechanistically, PF inhibited the CDC42/JNK signaling pathway by targeting CDC42. In particular, HuProtTM20K proteomics, molecular docking and MST revealed that PF is a novel CDC42 inhibitor. In LPS-treated Caco-2 cells, PF similarly inhibited oxidative stress, inflammation, and apoptosis and down-regulated the CDC42/JNK signaling pathway. Overall, PF inhibits oxidative stress, inflammation and apoptosis and repairs colonic epithelial damage through modulation of serum metabolites and inhibition of the CDC42/JNK signaling pathway, leading to alleviation of UC.PMID:39216118 | DOI:10.1016/j.intimp.2024.113039

Diabetes Metab Res Rev. 2024 Sep;40(6):e3839. doi: 10.1002/dmrr.3839.ABSTRACTBACKGROUND: Gestational diabetes mellitus (GDM) has a strong genetic predisposition. Integrating metabolomics with Mendelian randomisation (MR) analysis offers a potent method to uncover the metabolic factors causally linked to GDM pathogenesis.OBJECTIVES: This study aims to identify specific metabolites and metabolic pathways causally associated with GDM susceptibility through a comprehensive MR analysis. Additionally, it seeks to explore the potential of these identified metabolites as circulating biomarkers for early GDM detection and risk assessment. Furthermore, it aims to evaluate the implicated metabolic pathways as potential therapeutic targets for preventive or interventional strategies against GDM.METHODS: A two-sample MR study was conducted using summary statistics from a metabolite genome-wide association study (GWAS) of 8299 individuals and a GDM GWAS comprising 13,039 cases and 197,831 controls. Rigorous criteria were applied to select robust genetic instruments for 850 metabolites.RESULTS: MR analysis revealed 47 metabolites exhibiting putative causal associations with GDM risk. Among these, five metabolites demonstrated statistically significant associations after multiple-testing correction: Beta-citrylglutamate, Isobutyrylcarnitine (c4), 1,2-dilinoleoyl-GPC (18:2/18:2), Alliin and Cis-3,4-methyleneheptanoylcarnitine. Importantly, all these metabolites exhibited protective effects against GDM development. Additionally, metabolic pathway enrichment analysis implicated the methionine metabolism and spermidine and spermine biosynthesis pathways in the pathogenesis of GDM.CONCLUSION: This comprehensive MR study has robustly identified specific metabolites and metabolic pathways with causal links to GDM susceptibility. These findings provide novel insights into the metabolic underpinnings of GDM aetiology and offer promising translational implications. The identified metabolites could serve as potential circulating biomarkers for early detection and risk stratification, while the implicated metabolic pathways may represent therapeutic targets for preventive or interventional strategies against GDM.PMID:39216101 | DOI:10.1002/dmrr.3839

Appl Biochem Biotechnol. 2024 Aug 31. doi: 10.1007/s12010-024-05053-8. Online ahead of print.ABSTRACTMelochia corchorifolia is a well-known perennial herb and has been used in traditional medicine for the treatment of a wide number of diseases. However, the phytochemical investigation in the different organs of the M. corchorifolia was poorly understood. In the present study, the organ-specific metabolomic profiling of leaves, stems, and vegetable extract of M. corchorifolia was determined, and their potential antibiofilm activity with wound healing properties was evaluated. The UPLC-ESI-Q-TOF-MSE analysis showed 59 compounds in the leaf, stem, and vegetable extracts of M. corchorifolia. The crystal violet staining assay clearly showed that the extracts of M. corchorifolia have excellent antibiofilm activity against Proteus mirabilis and Salmonella typhi. The extracts of M. corchorifolia also caused the architecture of the bacterial biofilm by inhibiting the adherence to polystyrene and auto-aggregation and subsequently inhibiting the growth and colonization of the biofilm-forming bacteria P. mirabilis and S. typhi. The extracts of M. corchorifolia accelerate the wound healing process in BALB/c mice by completely closing the wound on the 20th day of treatment. Together, the phytochemicals present in the leaf, stem, and vegetable extracts of M. corchorifolia are responsible for potent antibiofilm and wound healing properties and could be used as an excellent remedy for treating chronic wounds and their associated infectious disease.PMID:39215903 | DOI:10.1007/s12010-024-05053-8