PubMed

Pharmaceuticals (Basel). 2023 Nov 2;16(11):1556. doi: 10.3390/ph16111556.ABSTRACTDemonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.PMID:38004421 | DOI:10.3390/ph16111556

Life (Basel). 2023 Oct 31;13(11):2149. doi: 10.3390/life13112149.ABSTRACTMud loach (Misgurnus mizolepis) has long been consumed in Korea. Recently, Chinese mud loaches were replaced with expensive Korean mud loaches, owing to taste and preference. Such issues occur in aquatic food distribution processes, leading to inferior food delivery. Previously, a study was conducted to confirm the origin of mud loaches using genetic analysis. However, untargeted metabolites profiling of mud loaches has not been reported. Untargeted metabolomics provides information on the overall metabolic profiling of a sample, allowing the identification of new metabolites. Here, we analyzed the metabolites of mud loaches of different geographical origins using liquid chromatography (LC)-quadrupole-time-of-flight mass spectrometry (MS). Orthogonal partial least squares discriminant analysis from LC/MS datasets showed a clear distinction between Korean and Chinese mud loaches, and univariate statistical analysis showed significantly different metabolites between them. N-acetylhistidine and anserine were selected as biomarkers for geographical origin discrimination using the receiver operating characteristic curve. N-acetylhistidine and anserine levels were significantly higher in Chinese than in Korean mud loaches. These results indicate that metabolic analysis can be used to discriminate between the geographical origins of mud loaches, curtailing the inadvertent substitution of mud loaches from different regions.PMID:38004289 | DOI:10.3390/life13112149

Nutrients. 2023 Nov 20;15(22):4849. doi: 10.3390/nu15224849.ABSTRACTBACKGROUND: Feeding intolerance (FI) is a significant concern in the care of preterm infants, impacting their growth and development. We previously reported that FI is linked to lower fecal calprotectin (FC) levels. This study aims to explore the postnatal dynamics and interplay between microbiota, metabolic profiles, and host immunity in preterm infants with and without FI.METHODS: Infants with gestational age <32 weeks or birth weight <1500 g were enrolled at the Children's Hospital of Fudan University between January 2018 and October 2020. Weekly fecal samples were analyzed for bacterial profiling, metabolome, and calprotectin levels, exploring their longitudinal development and interrelationships.RESULTS: Of the 118 very preterm infants studied, 48 showed FI. These infants experienced an interrupted microbial-immune trajectory, particularly at 3-4 weeks of age, marked by a reduced bacterial abundance, alpha diversity, and FC levels. Metabolic changes in FI were pronounced between 3 and 6 weeks. Pantothenic acid and two polyamine metabolites were closely associated with bacterial abundance and FC levels and negatively correlated with the duration to attain full enteral feeding.CONCLUSIONS: FI infants demonstrated compromised microbiome-immune interactions, potentially influenced by specific metabolites. This research underscored the importance of early microbial and metabolic development in the pathogenesis of FI in very preterm infants.PMID:38004243 | DOI:10.3390/nu15224849

Nutrients. 2023 Nov 16;15(22):4804. doi: 10.3390/nu15224804.ABSTRACTThe gut microbiota exert a profound influence on human health and metabolism, with microbial metabolites playing a pivotal role in shaping host physiology. This study investigated the impact of prolonged egg supplementation on insulin-like growth factor 1 (IGF-1) and circulating short-chain fatty acids (SCFAs). In a subset of a cluster-randomized trial, participants aged 8-14 years were randomly assigned into three groups: (1) Whole Egg (WE)-consuming 10 additional eggs per week [n = 24], (2) Protein Substitute (PS)-consuming yolk-free egg substitute equivalent to 10 eggs per week [n = 25], and (3) Control Group (C) [n = 26]. At week 35, IGF-1 levels in WE significantly increased (66.6 ± 27.7 ng/mL, p < 0.05) compared to C, with positive SCFA correlations, except acetate. Acetate was stable in WE, increasing in PS and C. Significant propionate differences occurred between WE and PS (14.8 ± 5.6 μmol/L, p = 0.010). WE exhibited notable changes in the relative abundance of the Bifidobacterium and Prevotella genera. Strong positive SCFA correlations were observed with MAT-CR-H4-C10 and Libanicoccus, while Roseburia, Terrisporobacter, Clostridia_UCG-014, and Coprococcus showed negative correlations. In conclusion, whole egg supplementation improves growth factors that may be related to bone formation and growth; it may also promote benefits to gut microbiota but may not affect SCFAs.PMID:38004198 | DOI:10.3390/nu15224804

Nutrients. 2023 Nov 15;15(22):4791. doi: 10.3390/nu15224791.ABSTRACTProgressive decline in pancreatic beta-cell function is central to the pathogenesis of type 2 diabetes (T2D). Here, we explore the relationship between the beta cell and its nutritional environment, asking how an excess of energy substrate leads to altered energy production and subsequent insulin secretion. Alterations in intracellular metabolic homeostasis are key markers of islets with T2D, but changes in cellular metabolite exchanges with their environment remain unknown. We answered this question using nuclear magnetic resonance-based quantitative metabolomics and evaluated the consumption or secretion of 31 extracellular metabolites from healthy and T2D human islets. Islets were also cultured under high levels of glucose and/or palmitate to induce gluco-, lipo-, and glucolipotoxicity. Biochemical analyses revealed drastic alterations in the pyruvate and citrate pathways, which appear to be associated with mitochondrial oxoglutarate dehydrogenase (OGDH) downregulation. We repeated these manipulations on the rat insulinoma-derived beta-pancreatic cell line (INS-1E). Our results highlight an OGDH downregulation with a clear effect on the pyruvate and citrate pathways. However, citrate is directed to lipogenesis in the INS-1E cells instead of being secreted as in human islets. Our results demonstrate the ability of metabolomic approaches performed on culture media to easily discriminate T2D from healthy and functional islets.PMID:38004183 | DOI:10.3390/nu15224791

Nutrients. 2023 Nov 13;15(22):4768. doi: 10.3390/nu15224768.ABSTRACTThe human gut microbiota is an ecosystem harboring trillions of microorganisms, encompassing bacteria, viruses, archaea, fungi, and protozoa [...].PMID:38004160 | DOI:10.3390/nu15224768

Nutrients. 2023 Nov 13;15(22):4767. doi: 10.3390/nu15224767.ABSTRACTIt has been found that Streptococcus thermophilus (S. thermophilus) influenced the gut microbiota and host metabolism with strain specificity in C57BL/6J mice in the previous study, though it remains unclear whether lactose as a dietary factor associated with dairy consumption is involved as the mediator in the interaction. In the present study, integrated analysis of 16S rRNA gene sequencing and untargeted metabolomics by liquid chromatography-mass spectrometry of fecal samples in C57BL/6J mice was applied to evaluate the effect of lactose on the regulation of gut microbiota by two S. thermophilus strains (4M6 and DYNDL13-4). The results showed that the influence of lactose supplementation on gut microbiota induced by S. thermophilus ingestion was strain-specific. Although two S. thermophilus strains ingestion introduced similar perturbations in the fecal microbiota and gut microbial metabolism, the regulation of DYNDL13-4 on the gut microbiota and metabolism was more affected by lactose than 4M6. More specifically, lactose and 4M6 supplementation mainly enriched pathways of d-glutamine and d-glutamate metabolism, alanine, aspartate, and glutamate metabolism, and tryptophan and phenylalanine metabolism in the gut, whereas 4M6 only enriched tryptophan and phenylalanine metabolism. DYNDL13-4-L (DYNDL13-4 with lactose) had significant effects on sulfur, taurine, and hypotaurine metabolism in the gut and on phenylalanine, tyrosine, tryptophan biosynthesis, and linoleic acid metabolism in serum relative to the DYNDL13-4. Our study demonstrated the strain-specific effect of lactose and S. thermophilus supplementation on gut microbiota and host metabolism. However, considering the complexity of the gut microbiota, further research is necessary to provide insights to facilitate the design of personalized fermented milk products as a dietary therapeutic strategy for improving host health.PMID:38004159 | DOI:10.3390/nu15224767

J Pers Med. 2023 Nov 10;13(11):1590. doi: 10.3390/jpm13111590.ABSTRACTCancer is the second major cause of disease-related death worldwide, and its accurate early diagnosis and therapeutic intervention are fundamental for saving the patient's life. Cancer, as a complex and heterogeneous disorder, results from the disruption and alteration of a wide variety of biological entities, including genes, proteins, mRNAs, miRNAs, and metabolites, that eventually emerge as clinical symptoms. Traditionally, diagnosis is based on clinical examination, blood tests for biomarkers, the histopathology of a biopsy, and imaging (MRI, CT, PET, and US). Additionally, omics biotechnologies help to further characterize the genome, metabolome, microbiome traits of the patient that could have an impact on the prognosis and patient's response to the therapy. The integration of all these data relies on gathering of several experts and may require considerable time, and, unfortunately, it is not without the risk of error in the interpretation and therefore in the decision. Systems biology algorithms exploit Artificial Intelligence (AI) combined with omics technologies to perform a rapid and accurate analysis and integration of patient's big data, and support the physician in making diagnosis and tailoring the most appropriate therapeutic intervention. However, AI is not free from possible diagnostic and prognostic errors in the interpretation of images or biochemical-clinical data. Here, we first describe the methods used by systems biology for combining AI with omics and then discuss the potential, challenges, limitations, and critical issues in using AI in cancer research.PMID:38003905 | DOI:10.3390/jpm13111590

Int J Mol Sci. 2023 Nov 17;24(22):16435. doi: 10.3390/ijms242216435.ABSTRACTImproving nitrogen (N) assimilation efficiency without yield penalties is important to sustainable food security. The chemical regulation approach of N assimilation efficiency is still less explored. We previously found that the co-application of brassinolide (BL) and pyraclostrobin (Pyr) synergistically boosted biomass and yield via regulating photosynthesis in Arabidopsis thaliana. However, the synergistic effect of BL and Pyr on N metabolism remains unclear. In this work, we examined the N and protein contents, key N assimilatory enzyme activities, and transcriptomic and metabolomic changes in the four treatments (untreated, BL, Pyr, and BL + Pyr). Our results showed that BL + Pyr treatment synergistically improved N and protein contents by 56.2% and 58.0%, exceeding the effects of individual BL (no increase) or Pyr treatment (36.4% and 36.1%). Besides synergistically increasing the activity of NR (354%), NiR (42%), GS (62%), and GOGAT (62%), the BL + Pyr treatment uniquely coordinated N metabolism, carbon utilization, and photosynthesis at the transcriptional and metabolic levels, outperforming the effects of individual BL or Pyr treatments. These results revealed that BL + Pyr treatments could synergistically improve N assimilation efficiency through improving N assimilatory enzyme activities and coordinated regulation of N and carbon metabolism. The identified genes and metabolites also informed potential targets and agrochemical combinations to enhance N assimilation efficiency.PMID:38003624 | DOI:10.3390/ijms242216435

Int J Mol Sci. 2023 Nov 16;24(22):16384. doi: 10.3390/ijms242216384.ABSTRACTPineapple color yellowing and quality promotion gradually manifest as pineapple fruit ripening progresses. To understand the molecular mechanism underlying yellowing in pineapples during ripening, coupled with alterations in fruit quality, comprehensive metabolome and transcriptome investigations were carried out. These investigations were conducted using pulp samples collected at three distinct stages of maturity: young fruit (YF), mature fruit (MF), and fully mature fruit (FMF). This study revealed a noteworthy increase in the levels of total phenols and flavones, coupled with a concurrent decline in lignin and total acid contents as the fruit transitioned from YF to FMF. Furthermore, the analysis yielded 167 differentially accumulated metabolites (DAMs) and 2194 differentially expressed genes (DEGs). Integration analysis based on DAMs and DEGs revealed that the biosynthesis of plant secondary metabolites, particularly the flavonol, flavonoid, and phenypropanoid pathways, plays a pivotal role in fruit yellowing. Additionally, RNA-seq analysis showed that structural genes, such as FLS, FNS, F3H, DFR, ANR, and GST, in the flavonoid biosynthetic pathway were upregulated, whereas the COMT, CCR, and CAD genes involved in lignin metabolism were downregulated as fruit ripening progressed. APX as well as PPO, and ACO genes related to the organic acid accumulations were upregulated and downregulated, respectively. Importantly, a comprehensive regulatory network encompassing genes that contribute to the metabolism of flavones, flavonols, lignin, and organic acids was proposed. This network sheds light on the intricate processes that underlie fruit yellowing and quality alterations. These findings enhance our understanding of the regulatory pathways governing pineapple ripening and offer valuable scientific insight into the molecular breeding of pineapples.PMID:38003574 | DOI:10.3390/ijms242216384

Int J Mol Sci. 2023 Nov 15;24(22):16378. doi: 10.3390/ijms242216378.ABSTRACTSaccharomyces cerevisiae is a promising host for the bioproduction of higher alcohols, such as 2,3-butanediol (2,3-BDO). Metabolically engineered S. cerevisiae strains that produce 2,3-BDO via glycolysis have been constructed. However, the specific 2,3-BDO production rates of engineered strains must be improved. To identify approaches to improving the 2,3-BDO production rate, we investigated the factors contributing to higher ethanol production rates in certain industrial strains of S. cerevisiae compared to laboratory strains. Sequence analysis of 11 industrial strains revealed the accumulation of many nonsynonymous substitutions in RIM15, a negative regulator of high fermentation capability. Comparative metabolome analysis suggested a positive correlation between the rate of ethanol production and the activity of the pyruvate-consuming pathway. Based on these findings, RIM15 was deleted, and the pyruvate-consuming pathway was activated in YHI030, a metabolically engineered S. cerevisiae strain that produces 2,3-BDO. The titer, specific production rate, and yield of 2,3-BDO in the test tube-scale culture using the YMS106 strain reached 66.4 ± 4.4 mM, 1.17 ± 0.017 mmol (g dry cell weight h)-1, and 0.70 ± 0.03 mol (mol glucose consumed)-1. These values were 2.14-, 2.92-, and 1.81-fold higher than those of the vector control, respectively. These results suggest that bioalcohol production via glycolysis can be enhanced in a metabolically engineered S. cerevisiae strain by deleting RIM15 and activating the pyruvate-consuming pathway.PMID:38003568 | DOI:10.3390/ijms242216378

Int J Mol Sci. 2023 Nov 13;24(22):16271. doi: 10.3390/ijms242216271.ABSTRACTMultiple sclerosis (MS) is a demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) damaging myelin and axons. Diagnosis is based on the combination of clinical findings, magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid (CSF). Metabolomics is a systematic study that allows us to track amounts of different metabolites in a chosen medium. The aim of this study was to establish metabolomic differences between the cerebrospinal fluid of patients in the early stages of multiple sclerosis and healthy controls, which could potentially serve as markers for predicting disease activity. We collected CSF from 40 patients after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS, and the CSF of 33 controls. Analyses of CSF samples were performed by using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector. Significant changes in concentrations of arginine, histidine, spermidine, glutamate, choline, tyrosine, serine, oleic acid, stearic acid and linoleic acid were observed. More prominently, Expanded Disability Status Scale values significantly correlated with lower concentrations of histidine. We conclude that these metabolites could potentially play a role as a biomarker of disease activity and predict presumable inflammatory changes.PMID:38003464 | DOI:10.3390/ijms242216271

Int J Mol Sci. 2023 Nov 13;24(22):16272. doi: 10.3390/ijms242216272.ABSTRACTInflammation is the host response of immune cells during infection and traumatic tissue injury. An uncontrolled inflammatory response leads to inflammatory cascade, which in turn triggers a variety of diseases threatening human and animal health. The use of existing inflammatory therapeutic drugs is constrained by their high cost and susceptibility to systemic side effects, and therefore new therapeutic candidates for inflammatory diseases need to be urgently developed. Natural products are characterized by wide sources and rich pharmacological activities, which are valuable resources for the development of new drugs. This study aimed to uncover the alleviating effect and potential mechanism of natural product Limonium aureum (LAH) on LPS-induced inflammatory responses in macrophages. The experimental results showed that the optimized conditions for LAH ultrasound-assisted extraction via response surface methodology were an ethanol concentration of 72%, a material-to-solvent ratio of 1:37 g/mL, an extraction temperature of 73 °C, and an extraction power of 70 W, and the average extraction rate of LAH total flavonoids was 0.3776%. Then, data of 1666 components in LAH ethanol extracts were obtained through quasi-targeted metabolomics analysis. The ELISA showed that LAH significantly inhibited the production of pro-inflammatory cytokines while promoting the secretion of anti-inflammatory cytokines. Finally, combined with the results of network pharmacology analysis and protein expression validation of hub genes, it was speculated that LAH may alleviate LPS-induced inflammatory responses of macrophages through the AKT1/RELA/PTGS2 signaling pathway and the MAPK3/JUN signaling pathway. This study preliminarily revealed the anti-inflammatory activity of LAH and the molecular mechanism of its anti-inflammatory action, and provided a theoretical basis for the development of LAH as a new natural anti-inflammatory drug.PMID:38003461 | DOI:10.3390/ijms242216272

Int J Mol Sci. 2023 Nov 13;24(22):16242. doi: 10.3390/ijms242216242.ABSTRACTThe vesicular transport system is important for substance transport in plants. In recent years, the regulatory relationship between the vesicular transport system and plant disease resistance has received widespread attention; however, the underlying mechanism remains unclear. MdSYP121 is a key protein in the vesicular transport system. The overexpression of MdSYP121 decreased the B. dothidea resistance of apple, while silencing MdSYP121 resulted in the opposite phenotype. A metabolome and transcriptome dataset analysis showed that MdSYP121 regulated apple disease resistance by significantly affecting sugar metabolism. HPLC results showed that the levels of many soluble sugars were significantly higher in the MdSYP121-OE calli. Furthermore, the expression levels of genes related to sugar transport were significantly higher in the MdSYP121-OE calli after B. dothidea inoculation. In addition, the relationships between the MdSYP121 expression level, the soluble sugar content, and apple resistance to B. dothidea were verified in an F1 population derived from a cross between 'Golden Delicious' and 'Fuji Nagafu No. 2'. In conclusion, these results suggested that MdSYP121 negatively regulated apple resistance to B. dothidea by influencing the soluble sugar content. These technologies and methods allow us to investigate the molecular mechanism of the vesicular transport system regulating apple resistance to B. dothidea.PMID:38003432 | DOI:10.3390/ijms242216242

Int J Mol Sci. 2023 Nov 12;24(22):16222. doi: 10.3390/ijms242216222.ABSTRACTOxygen deficiency is an environmental challenge which affects plant growth, the development and distribution in land and aquatic ecosystems, as well as crop yield losses worldwide. The capacity to exist in the conditions of deficiency or the complete lack of oxygen depends on a number of anatomic, developmental and molecular adaptations. The lack of molecular oxygen leads to an inhibition of aerobic respiration, which causes energy starvation and the acceleration of glycolysis passing into fermentations. We focus on systemic metabolic alterations revealed with the different approaches of metabolomics. Oxygen deprivation stimulates the accumulation of glucose, pyruvate and lactate, indicating the acceleration of the sugar metabolism, glycolysis and lactic fermentation, respectively. Among the Krebs-cycle metabolites, only the succinate level increases. Amino acids related to glycolysis, including the phosphoglycerate family (Ser and Gly), shikimate family (Phe, Tyr and Trp) and pyruvate family (Ala, Leu and Val), are greatly elevated. Members of the Asp family (Asn, Lys, Met, Thr and Ile), as well as the Glu family (Glu, Pro, Arg and GABA), accumulate as well. These metabolites are important members of the metabolic signature of oxygen deficiency in plants, linking glycolysis with an altered Krebs cycle and allowing alternative pathways of NAD(P)H reoxidation to avoid the excessive accumulation of toxic fermentation products (lactate, acetaldehyde, ethanol). Reoxygenation induces the downregulation of the levels of major anaerobically induced metabolites, including lactate, succinate and amino acids, especially members of the pyruvate family (Ala, Leu and Val), Tyr and Glu family (GABA and Glu) and Asp family (Asn, Met, Thr and Ile). The metabolic profiles during native and environmental hypoxia are rather similar, consisting in the accumulation of fermentation products, succinate, fumarate and amino acids, particularly Ala, Gly and GABA. The most intriguing fact is that metabolic alterations during oxidative stress are very much similar, with plant response to oxygen deprivation but not to reoxygenation.PMID:38003412 | DOI:10.3390/ijms242216222

Int J Mol Sci. 2023 Nov 10;24(22):16173. doi: 10.3390/ijms242216173.ABSTRACTMore than 12 million people around the world suffer a stroke every year, one every 3 s. Stroke has a variety of causes and is often the result of a complex interaction of risk factors related to age, genetics, gender, lifestyle, and some cardiovascular and metabolic diseases. Despite this evidence, it is not possible to prevent the onset of stroke. The use of innovative methods for metabolite analysis has been explored in the last years to detect new stroke biomarkers. We use NMR spectroscopy to identify small molecule variations between different stages of stroke risk. The Framingham Stroke Risk Score was used in people over 63 years of age living in long-term care facilities (LTCF) to calculate the probability of suffering a stroke. Using this parameter, three study groups were formed: low stroke risk (LSR, control), moderate stroke risk (MSR) and high stroke risk (HSR). Univariate statistical analysis showed seven metabolites with increasing plasma levels across different stroke risk groups, from LSR to HSR: isoleucine, asparagine, formate, creatinine, dimethylsulfone and two unidentified molecules, which we termed "unknown-1" and "unknown-3". These metabolic markers can be used for early detection and to detect increasing stages of stroke risk more efficiently.PMID:38003362 | DOI:10.3390/ijms242216173

Int J Mol Sci. 2023 Nov 9;24(22):16145. doi: 10.3390/ijms242216145.ABSTRACTBrucella, a zoonotic facultative intracellular pathogenic bacterium, poses a significant threat both to human health and to the development of the livestock industry. Alanine racemase (Alr), the enzyme responsible for alanine racemization, plays a pivotal role in regulating virulence in this bacterium. Moreover, Brucella mutants with alr gene deletions (Δalr) exhibit potential as vaccine candidates. However, the mechanisms that underlie the detrimental effects of alr knockouts on Brucella pathogenicity remain elusive. Here, initially, we conducted a bioinformatics analysis of Alr, which demonstrated a high degree of conservation of the protein within Brucella spp. Subsequent metabolomics studies unveiled alterations in amino acid pathways following deletion of the alr gene. Furthermore, alr deletion in Brucella suis S2 induced decreased resistance to stress, antibiotics, and other factors. Transmission electron microscopy of simulated macrophage intracellular infection revealed damage to the cell wall in the Δalr strain, whereas propidium iodide staining and alkaline phosphatase and lactate dehydrogenase assays demonstrated alterations in cell membrane permeability. Changes in cell wall properties were revealed by measurements of cell surface hydrophobicity and zeta potential. Finally, the diminished adhesion capacity of the Δalr strain was shown by immunofluorescence and bacterial enumeration assays. In summary, our findings indicate that the alr gene that regulates amino acid metabolism in Brucella influences the properties of the cell wall, which modulates bacterial adherence capability. This study is the first demonstration that Alr impacts virulence by modulating bacterial metabolism, thereby providing novel insights into the pathogenic mechanisms of Brucella spp.PMID:38003334 | DOI:10.3390/ijms242216145

Int J Mol Sci. 2023 Nov 8;24(22):16086. doi: 10.3390/ijms242216086.ABSTRACTLiver fibrosis (LF) is a late-stage process observed in various chronic liver diseases with bile and retinol metabolism closely associated with it. Adipose-derived mesenchymal stem cells (ADMSCs) have shown significant therapeutic potential in treating LF. In this study, the transplantation of ADMSCs was applied to a CCl4-induced LF model to investigate its molecular mechanism through a multi-omics joint analysis. The findings reveal that ADMSCs effectively reduced levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), gamma-glutamyltransferase (GGT), Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and α-Smooth muscle actin (α-SMA), thereby mitigating liver lesions, preventing liver parenchymal necrosis, and improving liver collagen deposition. Furthermore, 4751 differentially expressed genes (DEGs) and 270 differentially expressed metabolites (DMs) were detected via transcriptome and metabolomics analysis. Conjoint analysis showed that ADMSCs up-regulated the expression of Cyp7a1, Baat, Cyp27a1, Adh7, Slco1a4, Aldh1a1, and Adh7 genes to promote primary bile acids (TCDCA: Taurochenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; GCA: glycocholic acid, TCA: Taurocholic acid) synthesis, secretion and retinol metabolism. This suggests that ADMSCs play a therapeutic role in maintaining bile acid (BA) homeostasis and correcting disturbances in retinol metabolism.PMID:38003277 | DOI:10.3390/ijms242216086

Int J Mol Sci. 2023 Nov 7;24(22):16057. doi: 10.3390/ijms242216057.ABSTRACTEndometrial cancer (EC) is the most frequent gynecologic cancer in postmenopausal women. Pathogenetic mechanisms that are related to the onset and progression of the disease are largely still unknown. A multi-omics strategy can help identify altered pathways that could be targeted for improving therapeutical approaches. In this study we used a multi-omics approach on four EC cell lines for the identification of common dysregulated pathways in type 1 and 2 ECs. We analyzed proteomics and metabolomics of AN3CA, HEC1A, KLE and ISHIKAWA cell lines by mass spectrometry. The bioinformatic analysis identified 22 common pathways that are in common with both types of EC. In addition, we identified five proteins and 13 metabolites common to both types of EC. Western blotting analysis on 10 patients with type 1 and type 2 EC and 10 endometria samples confirmed the altered abundance of NPEPPS. Our multi-omics analysis identified dysregulated proteins and metabolites involved in EC tumor growth. Further studies are needed to understand the role of these molecules in EC. Our data can shed light on common pathways to better understand the mechanisms involved in the development and growth of EC, especially for the development of new therapies.PMID:38003247 | DOI:10.3390/ijms242216057

Int J Mol Sci. 2023 Nov 7;24(22):16045. doi: 10.3390/ijms242216045.ABSTRACTThe phytohormone gibberellic acids (GAs) play a crucial role in the processes of growth, organ development, and secondary metabolism. However, the mechanism of exogenous GA3 regulating the growth and flavonoid synthesis in Phellodendron chinense Schneid (P. chinense Schneid) seedlings remains unclear. In this study, the physicochemical properties, gene expression level, and secondary metabolite of P. chinense Schneid seedlings under GA3 treatment were investigated. The results showed that GA3 significantly improved the plant height, ground diameter, fresh weight, chlorophyll content, soluble substance content, superoxide dismutase, and peroxidase activities. This was accompanied by elevated relative expression levels of Pc(S)-GA2ox, Pc(S)-DELLA, Pc(S)-SAUR50, Pc(S)-PsaD, Pc(S)-Psb 27, Pc(S)-PGK, Pc(S)-CER3, and Pc(S)-FBA unigenes. Conversely, a notable reduction was observed in the carotenoid content, catalase activity and the relative expression abundances of Pc(S)-KAO, Pc(S)-GID1/2, and Pc(S)-GH 3.6 unigenes in leaves of P. chinense Schneid seedlings (p < 0.05). Furthermore, GA3 evidently decreased the contents of pinocembrin, pinobanksin, isosakuranetin, naringin, naringenin, (-)-epicatechin, tricetin, luteolin, and vitexin belonged to flavonoid in stem bark of P. chinense Schneid seedlings (p < 0.05). These results indicated that exogenous GA3 promoted growth through improving chlorophyll content and gene expression in photosynthesis and phytohormone signal pathway and inhibited flavonoid synthesis in P. chinense Schneid seedlings.PMID:38003235 | DOI:10.3390/ijms242216045