PubMed

Front Vet Sci. 2023 Jan 20;9:1039032. doi: 10.3389/fvets.2022.1039032. eCollection 2022.ABSTRACTINTRODUCTION: Pet foods fortified with fermentable fibers are often indicated for dogs with gastrointestinal conditions to improve gut health through the production of beneficial post-biotics by the pet's microbiome.METHODS: To evaluate the therapeutic underpinnings of pre-biotic fiber enrichment, we compared the fecal microbiome, the fecal metabolome, and the serum metabolome of 39 adult dogs with well-managed chronic gastroenteritis/enteritis (CGE) and healthy matched controls. The foods tested included a test food (TF1) containing a novel pre-biotic fiber bundle, a control food (CF) lacking the fiber bundle, and a commercially available therapeutic food (TF2) indicated for managing fiber-responsive conditions. In this crossover study, all dogs consumed CF for a 4-week wash-in period, were randomized to either TF1 or TF2 and fed for 4 weeks, were fed CF for a 4-week washout period, and then received the other test food for 4 weeks.RESULTS: Meaningful differences were not observed between the healthy and CGE dogs in response to the pre-biotic fiber bundle relative to CF. Both TF1 and TF2 improved stool scores compared to CF. TF1-fed dogs showed reduced body weight and fecal ash content compared to either CF or TF2, while stools of TF2-fed dogs showed higher pH and lower moisture content vs. TF1. TF1 consumption also resulted in unique fecal and systemic metabolic signatures compared to CF and TF2. TF1-fed dogs showed suppressed signals of fecal bacterial putrefactive metabolism compared to either CF or TF2 and increased saccharolytic signatures compared to TF2. A functional analysis of fecal tryptophan metabolism indicated reductions in fecal kynurenine and indole pathway metabolites with TF1. Among the three foods, TF1 uniquely increased fecal polyphenols and the resulting post-biotics. Compared to CF, consumption of TF1 largely reduced fecal levels of endocannabinoid-like metabolites and sphingolipids while increasing both fecal and circulating polyunsaturated fatty acid profiles, suggesting that TF1 may have modulated gastrointestinal inflammation and motility. Stools of TF1-fed dogs showed reductions in phospholipid profiles, suggesting fiber-dependent changes to colonic mucosal structure.DISCUSSION: These findings indicate that the use of a specific pre-biotic fiber bundle may be beneficial in healthy dogs and in dogs with CGE.PMID:36744230 | PMC:PMC9896628 | DOI:10.3389/fvets.2022.1039032

Front Pharmacol. 2023 Jan 18;13:1088750. doi: 10.3389/fphar.2022.1088750. eCollection 2022.ABSTRACTBackground: Intrahepatic cholestasis (IC) is a disorder of bile production, secretion, and excretion with various causes. Crocin I (CR) is effective in the treatment of IC, but its underlying mechanisms need to be further explored. We aimed to reveal the therapeutic mechanism of crocin I for IC by combining an integrated strategy of metabolomics and transcriptomics. Methods: The hepatoprotective effect of CR against cholestasis liver injury induced by α-naphthylisothiocyanate (ANIT) was evaluated in rats. The serum biochemical indices, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), total bilirubin (TBIL), direct bilirubin (DBIL), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), as well as the liver oxidative stress indexes and the pathological characteristics of the liver were analyzed. In addition, we also performed a serum metabolomics study using UPLC-Q Exactive HF-X technology to investigate the effect of CR on the serum of rats with ANIT-induced IC and screened potential biomarkers. The enrichment analysis of differential expressed genes (DEGs) was performed by transcriptomics. Finally, the regulatory targets of CR on potential biomarkers were obtained by combined analysis, and the relevant key targets were verified by western blotting. Results: CR improved serum and liver homogenate indexes and alleviated liver histological injury. Compared with ANIT group, the CR group had 76 differential metabolites, and 10 metabolic pathways were enriched. There were 473 DEGs significantly changed after CR treatment, most of which were enriched in the retinol metabolism, calcium signaling pathway, PPAR signaling pathway, circadian rhythm, chemokine signaling pathway, arachidonic acid metabolism, bile secretion, primary bile acid biosynthesis, and other pathways. By constructing the "compound-reaction-enzyme-gene" interaction network, three potential key-target regulation biomarkers were obtained, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), ATP-binding cassette transporter G5 (ABCG5), and sulfotransferase2A1(SULT2A1), which were further verified by western blotting. Compared with the ANIT group, the CR group significantly increased the expression of ABCG5 and SULT2A1, and the expression of HMGCR significantly decreased. Conclusion: Combined metabolomic and transcriptomic analyses show that CR has a therapeutic effect on IC through regulation of the biosynthesis of bile acids and bilirubin in the bile secretion pathway and regulation of the expression of HMGCR, ABCG5, and SULT2A1.PMID:36744213 | PMC:PMC9890161 | DOI:10.3389/fphar.2022.1088750

Nutr Metab Insights. 2023 Jan 31;16:11786388221148858. doi: 10.1177/11786388221148858. eCollection 2023.ABSTRACTDietary malpractice is a risk factor for obesity. This study tested the hypothesis that consumption of a high-fat diet alters mammary metabolome in pubertal mice. We performed untargeted metabolomic analysis of primary metabolism on mammary glands from pubertal mice fed the AIN93G standard diet or a high-fat diet (HFD) for 3 weeks. We identified 97 metabolites for statistical comparisons. The HFD altered the amino acid metabolism considerably. This included elevated expression of branched-chain amino acids, non-essential amino acids (aspartic acid and glutamic acid), and methionine sulfoxide (oxidized methionine) and an alteration in the aminoacyl-tRNA biosynthesis pathway. Furthermore, elevations of fumaric acid and malic acid (both are citrate cycle intermediates) and glyceric acid (its phosphate derivatives are intermediates of glycolysis) in HFD-fed mice suggest an acceleration of both citrate cycle and glycolysis. Lower expression of glycerol, oleic acid, and palmitoleic acid, as well as decreased mammary expression of genes encoding lipid metabolism (Acaca, Fads1, Fasn, Scd1, and Srebf1) in HFD-fed mice indicate an attenuated lipid metabolism in the presence of adequate dietary fat. In conclusion, consumption of the HFD for 3 weeks alters metabolic profile of pubertal mammary glands. This alteration may affect mammary development and growth in pubertal mice.PMID:36744049 | PMC:PMC9893363 | DOI:10.1177/11786388221148858

PNAS Nexus. 2023 Jan 27;2(1):pgac309. doi: 10.1093/pnasnexus/pgac309. eCollection 2023 Jan.ABSTRACTRapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.PMID:36744021 | PMC:PMC9896899 | DOI:10.1093/pnasnexus/pgac309

Cell Stress. 2023 Jan 23;7(1):1-6. doi: 10.15698/cst2023.01.275. eCollection 2023 Jan.ABSTRACTThe deletion of the gene coding for poly(ADP-ribose) polymerase-1 (PARP1) or its pharmacological inhibition protects mice against cerebral ischemia and Parkinson's disease. In sharp contrast, PARP1 inhibitors are in clinical use for the eradication of vulnerable cancer cells. It appears that excessive PARP1 activation is involved in a specific cell death pathway called parthanatos, while inhibition of PARP1 in cancer cells amplifies DNA damage to a lethal level. Hence, PARP1 plays a context-dependent role in cell fate decisions. In addition, it appears that PARP1 plays an ambiguous role in organismal aging.PMID:36743979 | PMC:PMC9877585 | DOI:10.15698/cst2023.01.275

Front Endocrinol (Lausanne). 2023 Jan 18;13:1103051. doi: 10.3389/fendo.2022.1103051. eCollection 2022.ABSTRACTAnuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of changing levels of THs during metamorphosis relies on pooled samples using methods known for high variability with sparse reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we targeted 12 THs and metabolites in the serum of Rana [Lithobates] catesbeiana (n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels were related to TH-relevant gene transcripts (thra, thrb, and thibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3',5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28 ± 10 and 2.3 ± 0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. While thra transcript levels remained constant and then decreased at the end of metamorphic climax, thrb and thibz were induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. The distinct T2 concentration profile suggests a biological role of this biomolecule in anuran postembryonic development and an additional aspect that may be a target of anthropogenic chemicals that can disrupt anuran metamorphosis and TH signalling. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones.PMID:36743912 | PMC:PMC9889540 | DOI:10.3389/fendo.2022.1103051

Front Plant Sci. 2023 Jan 20;13:1119152. doi: 10.3389/fpls.2022.1119152. eCollection 2022.NO ABSTRACTPMID:36743584 | PMC:PMC9897056 | DOI:10.3389/fpls.2022.1119152

Front Plant Sci. 2023 Jan 19;13:1098673. doi: 10.3389/fpls.2022.1098673. eCollection 2022.ABSTRACTHorticultural production is a vital catalyst for economic growth, yet insect infestations reduce horticultural crop yield and quality. Pesticides and other pest control methods are used during planting to eliminate pests that cause direct and indirect losses. In such situations, endophytic entomo-pathogenic fungi (EEPF) can act as a potential tools for biological control. They protect plants by boosting growth, nutrition, morpho-physiology and salt or iron tolerance. Antixenosis, antibiosis and plant tolerance change insect performance and preferences. EEPF- plant colonisation slows herbivore development, food consumption, oviposition and larval survival. EEPF changes plant physio-chemical properties like volatile emission profile and secondary metabolite production to regulate insect pest defences. EEPF produces chitinases, laccases, amylases, and cellulases for plant defence. Recent studies focused on EEPF species' significance, isolation, identification and field application. Realizing their full potential is difficult due to insufficient mass production, storage stability and formulation. Genetic-molecular and bioinformatics can help to build EEPF-based biological control systems. Metagenomics helps study microbial EEPF taxonomy and function. Multi-omics and system biology can decode EEPF interactions with host plants and microorganisms. NGS (Next Generation Sequencing), comparative genomics, proteomics, transcriptomics, metabolomics, metatranscriptomics and microarrays are used to evaluate plant-EEPF relationships. IPM requires understanding the abiotic and biotic elements that influence plant-EEPF interaction and the physiological mechanisms of EEPF colonisation. Due to restricted research, there are hundreds of unexplored EEPFs, providing an urgent need to uncover and analyse them.PMID:36743574 | PMC:PMC9894630 | DOI:10.3389/fpls.2022.1098673

Front Plant Sci. 2023 Jan 18;13:1067076. doi: 10.3389/fpls.2022.1067076. eCollection 2022.ABSTRACTDrought stress usually causes huge economic losses for tobacco industries. Drought stress exhibits multifaceted impacts on tobacco systems through inducing changes at different levels, such as physiological and chemical changes, changes of gene transcription and metabolic changes. Understanding how plants respond and adapt to drought stress helps generate engineered plants with enhanced drought resistance. In this study, we conducted multiple time point-related physiological, biochemical,transcriptomic and metabolic assays using K326 and its derived mutant 28 (M28) with contrasting drought tolerance. Through integrative analyses of transcriptome and metabolome,we observed dramatic changes of gene expression and metabolic profiles between M28 and K326 before and after drought treatment. we found that some of DEGs function as key enzymes responsible for ABA biosynthesis and metabolic pathway, thereby mitigating impairment of drought stress through ABA signaling dependent pathways. Four DEGs were involved in nitrogen metabolism, leading to synthesis of glutamate (Glu) starting from NO-3 /NO-2 that serves as an indicator for stress responses. Importantly, through regulatory network analyses, we detected several drought induced TFs that regulate expression of genes responsible for ABA biosynthesis through network, indicating direct and indirect involvement of TFs in drought responses in tobacco. Thus, our study sheds some mechanistic insights into how plant responding to drought stress through transcriptomic and metabolic changes in tobacco. It also provides some key TF or non-TF gene candidates for engineering manipulation for breeding new tobacco varieties with enhanced drought tolerance.PMID:36743571 | PMC:PMC9891310 | DOI:10.3389/fpls.2022.1067076

Front Plant Sci. 2023 Jan 19;13:1048217. doi: 10.3389/fpls.2022.1048217. eCollection 2022.ABSTRACTGenetic improvement of temperate fruit and nut crops through conventional breeding methods is not sufficient alone due to its extreme time-consuming, cost-intensive, and hard-to-handle approach. Again, few other constraints that are associated with these species, viz., their long juvenile period, high heterozygosity, sterility, presence of sexual incompatibility, polyploidy, etc., make their selection and improvement process more complicated. Therefore, to promote precise and accurate selection of plants based on their genotypes, supplement of advanced biotechnological tools, viz., molecular marker approaches along with traditional breeding methods, is highly required in these species. Different markers, especially the molecular ones, enable direct selection of genomic regions governing the trait of interest such as high quality, yield, and resistance to abiotic and biotic stresses instead of the trait itself, thus saving the overall time and space and helping screen fruit quality and other related desired traits at early stages. The availability of molecular markers like SNP (single-nucleotide polymorphism), DArT (Diversity Arrays Technology) markers, and dense molecular genetic maps in crop plants, including fruit and nut crops, led to a revelation of facts from genetic markers, thus assisting in precise line selection. This review highlighted several aspects of the molecular marker approach that opens up tremendous possibilities to reveal valuable information about genetic diversity and phylogeny to boost the efficacy of selection in temperate fruit crops through genome sequencing and thus cultivar improvement with respect to adaptability and biotic and abiotic stress resistance in temperate fruit and nut species.PMID:36743560 | PMC:PMC9893892 | DOI:10.3389/fpls.2022.1048217

Front Plant Sci. 2023 Jan 20;13:1097076. doi: 10.3389/fpls.2022.1097076. eCollection 2022.ABSTRACTSalicornia europaea is one of the world's salt-tolerant plant species and is recognized as a model plant for studying the metabolism and molecular mechanisms of halophytes under salinity. To investigate the metabolic responses to salinity stress in S. europaea, this study performed a widely targeted metabolomic analysis after analyzing the physiological characteristics of plants exposed to various NaCl treatments. S. europaea exhibited excellent salt tolerance and could withstand extremely high NaCl concentrations, while lower NaCl conditions (50 and 100 mM) significantly promoted growth by increasing tissue succulence and maintaining a relatively stable K+ concentration. A total of 552 metabolites were detected, 500 of which were differently accumulated, mainly consisting of lipids, organic acids, saccharides, alcohols, amino acids, flavonoids, phenolic acids, and alkaloids. Sucrose, glucose, p-proline, quercetin and its derivatives, and kaempferol derivatives represented core metabolites that are responsive to salinity stress. Glycolysis, flavone and flavonol biosynthesis, and phenylpropanoid biosynthesis were considered as the most important pathways responsible for salt stress response by increasing the osmotic tolerance and antioxidant activities. The high accumulation of some saccharides, flavonoids, and phenolic acids under 50 mM NaCl compared with 300 mM NaCl might contribute to the improved salt tolerance under the 50 mM NaCl treatment. Furthermore, quercetin, quercetin derivatives, and kaempferol derivatives showed varied change patterns in the roots and shoots, while coumaric, caffeic, and ferulic acids increased significantly in the roots, implying that the coping strategies in the shoots and roots varied under salinity stress. These findings lay the foundation for further analysis of the mechanism underlying the response of S. europaea to salinity.PMID:36743536 | PMC:PMC9896792 | DOI:10.3389/fpls.2022.1097076

Front Plant Sci. 2023 Jan 18;14:1073848. doi: 10.3389/fpls.2023.1073848. eCollection 2023.ABSTRACTMedicinal plants are natural sources to unravel novel bioactive compounds to satisfy human pharmacological potentials. The world's demand for herbal medicines is increasing year by year; however, large-scale production of medicinal plants and their derivatives is still limited. The rapid development of modern technology has stimulated multi-omics research in medicinal plants, leading to a series of breakthroughs on key genes, metabolites, enzymes involved in biosynthesis and regulation of active compounds. Here, we summarize the latest research progress on the molecular intricacy of medicinal plants, including the comparison of genomics to demonstrate variation and evolution among species, the application of transcriptomics, proteomics and metabolomics to explore dynamic changes of molecular compounds, and the utilization of potential resources for natural drug discovery. These multi-omics research provide the theoretical basis for environmental adaptation of medicinal plants and allow us to understand the chemical diversity and composition of bioactive compounds. Many medicinal herbs' phytochemical constituents and their potential health benefits are not fully explored. Given their large diversity and global distribution as well as the impacts of growth duration and environmental factors on bioactive phytochemicals in medicinal plants, it is crucial to emphasize the research needs of using multi-omics technologies to address basic and applied problems in medicinal plants to aid in developing new and improved medicinal plant resources and discovering novel medicinal ingredients.PMID:36743502 | PMC:PMC9891177 | DOI:10.3389/fpls.2023.1073848

Front Plant Sci. 2023 Jan 20;14:1065219. doi: 10.3389/fpls.2023.1065219. eCollection 2023.ABSTRACTFloral fragrance is an important trait that contributes to the ornamental properties and pollination of crabapple. However, research on the physiological and molecular biology of the floral volatile compounds of crabapple is rarely reported. In this study, metabolomic and transcriptomic analyses of the floral volatile compounds of standard Malus robusta flowers (Mr), and progeny with strongly and weakly fragrant flowers (SF and WF, respectively), were conducted. Fifty-six floral volatile compounds were detected in the plant materials, mainly comprising phenylpropane/benzene ring-type compounds, fatty acid derivatives, and terpene compounds. The volatile contents were significantly increased before the early flowering stage (ES), and the contents of SF flowers were twice those of WF and Mr flowers. Odor activity values were determined for known fragrant volatiles and 10-11 key fragrant volatiles were identified at the ES. The predominant fragrant volatiles were methyl benzoate, linalool, leaf acetate, and methyl anthranilate. In the petals, stamens, pistil, and calyx of SF flowers, 26 volatiles were detected at the ES, among which phenylpropane/benzene ring-type compounds were the main components accounting for more than 75% of the total volatile content. Functional analysis of transcriptome data revealed that the phenylpropanoid biosynthesis pathway was significantly enriched in SF flowers. By conducting combined analyses between volatiles and differentially expressed genes, transcripts of six floral scent-related genes were identified and were associated with the contents of the key fragrant volatiles, and other 23 genes were potentially correlated with the key volatile compounds. The results reveal possible mechanisms for the emission of strong fragrance by SF flowers, and provide a foundation for improvement of the floral fragrance and development of new crabapple cultivars.PMID:36743501 | PMC:PMC9895795 | DOI:10.3389/fpls.2023.1065219

Front Cell Infect Microbiol. 2023 Jan 20;13:1091825. doi: 10.3389/fcimb.2023.1091825. eCollection 2023.ABSTRACTNon-small cell lung cancer (NSCLC) is the predominant form of lung cancer and is one of the most fatal cancers worldwide. Recently, the International Association for the Study of Lung Cancer (IASLC) proposed a novel grading system based on the predominant and high-grade histological patterns for invasive pulmonary adenocarcinoma (IPA). To improve outcomes for NSCLC patients, we combined serum metabolomics and fecal microbiology to screen biomarkers in patients with early-stage NSCLC and identified characteristic microbial profiles in patients with different grades of IPA. 26 genera and 123 metabolites were significantly altered in the early-stage NSCLC patients. Agathobacter, Blautia, Clostridium, and Muribaculacea were more abundant in the early-stage NSCLC patients compared with healthy controls. For the different grades of IPA, the characteristic microorganisms are as follows: Blautia and Marinobacter in IPA grade type 1; Dorea in IPA grade type 2; and Agathobacter in IPA grade type 3. In the metabolome results, the early-stage NSCLC group mainly included higher levels of sphingolipids (D-erythro-sphingosine 1-phosphate, palmitoyl sphingomyelin), fatty acyl (Avocadyne 1-acetate, 12(S)-HETE, 20-Carboxy-Leukotriene B4, Thromboxane B3, 6-Keto-prostaglandin f1alpha, Sebacic acid, Tetradecanedioic acid) and glycerophospholipids (LPC 20:2, LPC 18:0, LPC 18:4, LPE 20:2, LPC 20:1, LPC 16:1, LPC 20:0, LPA 18:2, LPC 17:1, LPC 17:2, LPC 19:0). Dysregulation of pathways, such as sphingolipid metabolism and sphingolipid signaling pathway may become an emerging therapeutic strategy for early-NSCLC. Correlation analysis showed that gut microbiota and serum metabolic profiles were closely related, while Muribaculacea and Clostridium were the core genera. These findings provide new biomarkers for the diagnosis of early-stage NSCLC and the precise grading assessment of prognostic-related IPAs, which are of clinical importance and warrant further investigation of the underlying molecular mechanisms.PMID:36743312 | PMC:PMC9895385 | DOI:10.3389/fcimb.2023.1091825

Front Mol Biosci. 2023 Jan 19;10:1116398. doi: 10.3389/fmolb.2023.1116398. eCollection 2023.ABSTRACTPalbociclib is a specific CDK4/6 inhibitor that has been widely applied in multiple types of tumors. Different from cytotoxic drugs, the anticancer mechanism of palbociclib mainly depends on cell cycle inhibition. Therefore, the resistance mechanism is different. For clinical cancer patients, drug resistance is inevitable for almost all cancer therapies including palbociclib. We have trained palbociclib resistant cells in vitro to simulate the clinical situation and applied LC-MS multi-omics analysis methods including proteomic, metabolomic, and glycoproteomic techniques, to deeply understand the underly mechanism behind the resistance. As a result of proteomic analysis, the resistant cells were found to rely on altered metabolic pathways to keep proliferation. Metabolic processes related to carbohydrates, lipids, DNA, cellular proteins, glucose, and amino acids were observed to be upregulated. Most dramatically, the protein expressions of COX-1 and NDUFB8 have been detected to be significantly overexpressed by proteomic analysis. When a COX-1 inhibitor was hired to combine with palbociclib, a synergistic effect could be obtained, suggesting the altered COX-1 involved metabolic pathway is an important reason for the acquired palbociclib resistance. The KEGG pathway of N-glycan biosynthesis was identified through metabolomics analysis. N-glycoproteomic analysis was therefore included and the global glycosylation was found to be elevated in the palbociclib-resistant cells. Moreover, integration analysis of glycoproteomic data allowed us to detect a lot more proteins that have been glycosylated with low abundances, these proteins were considered to be overwhelmed by those highly abundant proteins during regular proteomic LC-MS detection. These low-abundant proteins are mainly involved in the cellular biology processes of cell migration, the regulation of chemotaxis, as well as the glycoprotein metabolic process which offered us great more details on the roles played by N-glycosylation in drug resistance. Our result also verified that N-glycosylation inhibitors could enhance the cell growth inhibition of palbociclib in resistant cells. The high efficiency of the integrated multi-omics analysis workflow in discovering drug resistance mechanisms paves a new way for drug development. With a clear understanding of the resistance mechanism, new drug targets and drug combinations could be designed to resensitize the resistant tumors.PMID:36743215 | PMC:PMC9892630 | DOI:10.3389/fmolb.2023.1116398

Front Nutr. 2023 Jan 19;10:1087256. doi: 10.3389/fnut.2023.1087256. eCollection 2023.ABSTRACTYellowhorn tea (YT) is traditionally used as a lipid-lowering beverage in Mongolian minorities. However, the pharmacological effects of YT extract and its specific metabolic changes in hyperlipidemia models are not fully understood. The aim of this study was to identify biomarkers using untargeted metabolomics techniques and to investigate the mechanisms underlying the changes in metabolic pathways associated with lipid lowering, anti-inflammation and anti-oxidant in hyperlipidemic mice. A high-fat diet (HFD)-induced hyperlipidemic mouse model was established. YT extract was administered as oral gavage at 0.15, 0.3, and 0.6 g/kg doses for 10 weeks. HFD-induced hyperlipidemia and the therapeutic effect of YT extract were evaluated based on histopathology and by assessing blood lipid levels. Liver inflammatory factors and oxidative stress indices were determined using enzyme-linked immunosorbent assays. Liver metabolites were evaluated using untargeted metabolomics. Biochemical and histological examinations showed that YT extract significantly reduced body-weight gain (p < 0.01) and fat deposition in tissues. YT extract significantly reduced the levels of serum and liver triglyceride and total cholesterol; inflammatory factors [interleukin (IL)-6, IL-1β, and tumor necrosis factor-α]; malondialdehyde; and leptin (p < 0.05) in hyperlipidemic mice. YT extract also significantly increased the levels of oxidative stress indicators (superoxide dismutase, catalase, and glutathione peroxidase) and adiponectin. Metabolomics studies revealed several endogenous molecules were altered by the high-fat diet and recovery following intervention with YT extract. The metabolites that were significantly different in the liver after YT intake included citicoline, acetylcholine, pyridoxine, and NAD. Pathway analysis indicated that YT extract ameliorated HFD-induced hyperlipidemia in mice via three major metabolic pathways, namely, glycerophospholipid metabolism, vitamin B6 metabolism, and nicotinate and nicotinamide metabolism. This study demonstrates YT extract has profound effects on the alleviation of HFD-induced hyperlipidemia, inflammation and oxidative stress.PMID:36742424 | PMC:PMC9894254 | DOI:10.3389/fnut.2023.1087256

Front Endocrinol (Lausanne). 2023 Jan 20;14:1045384. doi: 10.3389/fendo.2023.1045384. eCollection 2023.ABSTRACTOBJECTIVE: To study the effect of Guilu Erxian ointment on the outcome of IVF-ET in older patients with poor ovarian response infertility of kidney-qi deficiency type, and to verify and analyze the mechanism of action of traditional Chinese medicine on improving older patients with poor ovarian response infertility of kidney-qi deficiency type from the perspective of metabolomics using targeted metabolomics technology, identify the related metabolic pathways, and provide metabolic biomarker basis and clinical treatment ideas for improving older patients with poor ovarian response infertility.METHODS: This study was a double-blind, randomized, placebo-controlled trial, and a total of 119 infertile patients who underwent IVF-ET at Shandong Center for Reproduction and Genetics of Integrated Traditional Chinese and Western Medicine were selected. Eighty older patients with infertility undergoing IVF were randomly divided into older treatment group and older placebo group, and another 39 young healthy women who underwent IVF-ET or ICSI due to male factors were selected as the normal control group. Flexible GnRH antagonist protocol was used for ovulation induction in all three groups, and Guilu Erxian ointment and placebo groups started taking Guilu Erxian ointment and placebo from the third day of menstruation until IVF surgery. And ultra-high performance liquid chromatography-triple quadrupole mass spectrometer (UHPLC-QTRAP MS) was used to detect metabolites in the three groups of samples.RESULTS: Compared with the placebo group, the number of oocytes retrieved, 2PN fertilization, high-quality embryos, total number of available embryos and estrogen on HCG day were increased in the treatment group, and the differences were statistically significant (P > 0.05), but the clinical pregnancy rate of fresh embryos and frozen embryos were not statistically significant (P > 0.05). The results of targeted metabolomics analysis showed that follicular fluid in the treatment group clustered with the normal young group and deviated from the placebo group. A total of 55 significant differential metabolites were found in the follicular fluid of older patients with poor ovarian response of kidney-qi deficiency type and patients in the normal young group, after Guilu Erxian ointment intervention, Metabolites such as L-Aspartic acid, Glycine, L-Serine, Palmitoleic Acid, Palmitelaidic acid, L-Alanine, Gamma-Linolenic acid, Alpha-Linolenic Acid, and N-acetyltryptophan were down-regulated, mainly involving amino acid metabolism and fatty acid metabolism.CONCLUSION: Guilu Erxian ointment can effectively improve the clinical symptoms and IVF outcomes of older patients with poor ovarian response of kidney-qi deficiency type. There were differences in follicular fluid metabolites between older patients with poor ovarian response of kidney-qi deficiency type and normal women. L-Aspartic acid, L-Alanine, Aminoadipic acid, L-Asparagine, L-Arginine, L-Serine, Gamma- Linolenic acid, Pentadecanoic acid and Alpha-Linolenic Acid are closely related to older patients with poor ovarian response due to deficiency of kidney-qi and may be inferred as biomarkers. The mechanism of Guilu Erxian ointment intervention may be mainly through amino acid metabolism and fatty acid metabolism regulation.PMID:36742408 | PMC:PMC9897313 | DOI:10.3389/fendo.2023.1045384

Front Endocrinol (Lausanne). 2023 Jan 18;14:1120221. doi: 10.3389/fendo.2023.1120221. eCollection 2023.ABSTRACTBACKGROUND: Huang Lian (HL), one of the traditional Chinese medicines (TCMs) that contains multiple active components including berberine (BBR), has been used to treat symptoms associated with diabetes for thousands of years. Compared to the monomer of BBR, HL exerts a better glucose-lowering activity and plays different roles in regulating gut microbiota. However, it remains unclear what role the gut microbiota plays in the anti-diabetic activity of HL.METHODS: In this study, a type 2 diabetes mellitus (T2DM) mouse model was induced with a six-week high-fat diet (HFD) and a one-time injection of streptozotocin (STZ, 75 mg/kg). One group of these mice was administrated HL (50 mg/kg) through oral gavage two weeks after HFD feeding commenced and continued for four weeks; the other mice were given distilled water as disease control. Comprehensive analyses of physiological indices related to glycolipid metabolism, gut microbiota, untargeted metabolome, and hepatic genes expression, function prediction by PICRUSt2 were performed to identify potential mechanism.RESULTS: We found that HL, in addition to decreasing body fat accumulation, effectively improved insulin resistance by stimulating the hepatic insulin-mediated signaling pathway. In comparison with the control group, HL treatment constructed a distinct gut microbiota and bile acid (BA) profile. The HL-treated microbiota was dominated by bacteria belonging to Bacteroides and the Clostridium innocuum group, which were associated with BA metabolism. Based on the correlation analysis, the altered BAs were closely correlated with the improvement of T2DM-related markers.CONCLUSION: These results indicated that the anti-diabetic activity of HL was achieved, at least partly, by regulating the structure of the gut microbiota and the composition of BAs.PMID:36742405 | PMC:PMC9889990 | DOI:10.3389/fendo.2023.1120221

Front Endocrinol (Lausanne). 2023 Jan 20;14:1117111. doi: 10.3389/fendo.2023.1117111. eCollection 2023.ABSTRACTINTRODUCTION: Gnathodiaphyseal dysplasia (GDD; OMIM#166260) is a rare autosomal dominant disorder characterized by diaphyseal sclerosis of tubular bones and cemento-osseous lesions in mandibles. GDD is caused by point mutations in the ANO5 gene. However, the mechanisms underlying GDD have not been disclosed. We previously generated the first knock-in mouse model for GDD expressing a human mutation (p.Cys360Tyr) in ANO5 and homozygous Ano5 knock-in (Ano5KI/KI ) mice exhibited representative traits of human GDD especially including enhanced osteogenesis.METHODS: Metabolomics and transcriptomics analyses were conducted for wildtype (Ano5+/+ ) and Ano5KI/KI mature mouse calvarial osteoblasts (mCOBs) grown in osteogenic cultures for 14 days to identify differential intracellular metabolites and genes involved in GDD. Subsequently, related differential genes were validated by qRT-PCR. Cell proliferation was confirmed by CCK8 assay and calcium content in mineral nodules was detected using SEM-EDS.RESULTS: Metabolomics identified 42 differential metabolites that are primarily involved in amino acid and pyrimidine metabolism, and endocrine and other factor-regulated calcium reabsorption. Concomitantly, transcriptomic analysis revealed 407 differentially expressed genes in Ano5KI/KI osteoblasts compared with wildtype. Gene ontology and pathway analysis indicated that Ano5Cys360Tyr mutation considerably promoted cell cycle progression and perturbed calcium signaling pathway, which were confirmed by validated experiments. qRT-PCR and CCK-8 assays manifested that proliferation of Ano5KI/KI mCOBs was enhanced and the expression of cell cycle regulating genes (Mki67, Ccnb1, and Ccna2) was increased. In addition, SEM-EDS demonstrated that Ano5KI/KI mCOBs developed higher calcium contents in mineral nodules than Ano5+/+ mCOBs, while some calcium-related genes (Cacna1, Slc8a1, and Cyp27b1) were significantly up-regulated. Furthermore, osteocalcin which has been proved to be an osteoblast-derived metabolic hormone was upregulated in Ano5KI/KI osteoblast cultures.DISCUSSION: Our data demonstrated that the Ano5Cys360Tyr mutation could affect the metabolism of osteoblasts, leading to unwonted calcium homeostasis and cellular proliferation that can contribute to the underlying pathogenesis of GDD disorders.PMID:36742392 | PMC:PMC9895949 | DOI:10.3389/fendo.2023.1117111

Evid Based Complement Alternat Med. 2022 Nov 30;2022:5080282. doi: 10.1155/2022/5080282. eCollection 2022.ABSTRACTOBJECTIVE: Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by abnormal movements, phonations, and tics, but an accurate TS diagnosis remains challenging and indeed depends on its description of clinical symptoms. Our study was conducted to discover and verify some metabolite biomarkers based on nontargeted and targeted metabolomics.METHODS: We conducted untargeted ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) for preliminary screening of potential biomarkers on 30 TS patients and 10 healthy controls and then performed validation experiments based on targeted ultrahigh-performance liquid chromatography triple quadrupole-MS (UHPLC/MS/MS) on 35 TS patients and 14 healthy controls.RESULTS: 1775 differentially expressed metabolites were identified by partial least squares discriminant analysis (PLS-DA), fold-change analysis, T-test, and hierarchical clustering analysis (adjusted p value <0.05 and |logFC| > 1). TS plasma samples were found to be differentiated from healthy samples in our approach. Furthermore, aspartate and asparagine metabolism pathways were considered to be a significant enrichment pathway in TS progression based on metabolite pathway enrichment analysis. For the 8 metabolites involved in this pathway that we detected, we then performed validation experiments based on targeted UHPLC/MS/MS. The t-test, Mann-Whitney U test, and receiver operating characteristic (ROC) curve analysis were used to determine potential biomarkers. Ultimately, L-arginine and L-pipecolic acid were validated as significantly differentiated metabolites (p < 0.05), with an AUC of 70.0% and 80.3%, respectively.CONCLUSION: L-pipecolic acid was defined as a potential biomarker for TS diagnosis by the combined application of nontargeted and targeted metabolomic analysis.PMID:36742270 | PMC:PMC9894715 | DOI:10.1155/2022/5080282