PubMed

Front Pharmacol. 2022 Oct 31;13:966218. doi: 10.3389/fphar.2022.966218. eCollection 2022.ABSTRACTAnxiety disorder is one of the most common mental diseases. It is mainly characterized by a sudden, recurring but indescribable panic, fear, tension and/or anxiety. Yangshendingzhi granules (YSDZ) are widely used in the treatment of anxiety disorders, but its active ingredients and underlying mechanisms are not yet clear. This study integrates network pharmacology and metabolomics to investigate the potential mechanism of action of YSDZ in a rat model of anxiety. First, potential active ingredients and targets were screened by network pharmacology. Then, predictions were verified by molecular docking, molecular dynamics and western blotting. Metabolomics was used to identify differential metabolites and metabolic pathways. All results were integrated for a comprehensive analysis. Network pharmacology analysis found that Carotene, β-sitosterol, quercetin, Stigmasterol, and kaempferol in YSDZ exert anxiolytic effects mainly by acting on IL1β, GABRA1, PTGS1, ESR1, and TNF targets. Molecular docking results showed that all the affinities were lower than -5 kcal/mol, and the average affinities were -7.7764 kcal/mol. Molecular dynamics simulation results showed that RMSD was lower than 2.5 A, and the overall conformational changes of proteins were small, indicating that the small molecules formed stable complexes with proteins. The results of animal experiments showed that YSDZ exerts anxiolytic effects by regulating GABRA1 and TNF-α, ameliorating pathological damage in hippocampal CA1, and regulating metabolic pathways such as thiamine, cysteine and methionine metabolism, lysine biosynthesis and degradation. Altogether, we reveal multiple mechanisms through which YSDZ exerts its anti-anxiety effects, which may provide a reference for its clinical application and drug development.PMID:36386232 | PMC:PMC9659911 | DOI:10.3389/fphar.2022.966218

Front Pharmacol. 2022 Oct 26;13:1012063. doi: 10.3389/fphar.2022.1012063. eCollection 2022.ABSTRACTLung cancer is one of the malignant tumors with the fastest incidence rate and mortality growth and the greatest threat to human health and life. Marsdenia tenacissima is an antitumor of Chinese medicine. However, Marsdenia tenacissima has low bioavailability in the human body and most of its main active substances are aglycones, such as Tenacigenin A, Tenacigenin B. This study aims to produce biotransformation products rich in pungent saponins by using Marsdenia tenacissima as a fermentation medium of Ganoderma lucidum. Non-targeted metabolomics analysis was carried out on the fermentation products after the optimization process. A total of 249 differential metabolites were detected, and the content of saponins increased from 0.1% to 0.41% and most of them were tenacigenin. Furthermore, the biotransformation of C21 steroidal glycosides in Marsdenia tenacissima was the central reaction in this fermentation process. Pharmacodynamics resewed that the anticancer effect of Marsdenia tenacissima was significantly enhanced after fermentation, mainly through inhibiting the growth and apoptosis of cancer cells.PMID:36386222 | PMC:PMC9643841 | DOI:10.3389/fphar.2022.1012063

Front Pharmacol. 2022 Nov 1;13:1037563. doi: 10.3389/fphar.2022.1037563. eCollection 2022.ABSTRACTAmygdalus mongolica oil is rich in unsaturated fatty acids such as inoleic acid (47.11%) and oleic acid (23.81%). Our research demonstrates that it exerts a protective effect on rat models of pulmonary fibrosis, however, little is known regarding the underlying mechanism of action. This study aimed to characterize the therapeutic mechanism of action of A. mongolica oil on bleomycin-induced pulmonary fibrosis in rats. A. mongolica oil appears to regulate the levels of potential key serum biomarkers which include tetrahydrobiopterin, L-serine, citrulline and estradiol to participate in folate biosynthesis, glycine, serine and threonine metabolism, arginine biosynthesis and steroid hormone biosynthesis. And it also enriched intestinal microbial abundance, homogeneity and modulated the abundance of Duncaniell, Desulfovibrio, Peptococcaceae_unclassified, Dubosiella, Tyzzerella, Lachnospiraceae_NK4A136_group, Lactobacillus, Clostridiales_unclassified to exert a protective effect against pulmonary fibrosis. A. mongolica oil appears to confer protective effects against pulmonary fibrosis by affecting the level of pulmonary fibrosis metabolites and the abundance of related intestinal flora through multiple targets, as evidenced by our untargeted LC-MS/MS metabonomics evaluation and 16S rDNA sequencing technology.PMID:36386194 | PMC:PMC9663812 | DOI:10.3389/fphar.2022.1037563

Front Pharmacol. 2022 Oct 28;13:1066875. doi: 10.3389/fphar.2022.1066875. eCollection 2022.NO ABSTRACTPMID:36386182 | PMC:PMC9650449 | DOI:10.3389/fphar.2022.1066875

Front Pharmacol. 2022 Oct 24;13:1044808. doi: 10.3389/fphar.2022.1044808. eCollection 2022.ABSTRACTBackground: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is an adverse reaction with a high incidence and the greatest impact on tuberculosis treatment. However, there is a lack of effective biomarkers for the early prediction of ATB-DILI. Herein, this study uses UPLC‒MS/MS to reveal the plasma metabolic profile and lipid profile of ATB-DILI patients before drug administration and screen new biomarkers for predicting ATB-DILI. Methods: A total of 60 TB patients were enrolled, and plasma was collected before antituberculosis drug administration. The untargeted metabolomics and lipidomics analyses were performed using UPLC‒MS/MS, and the high-resolution mass spectrometer Q Exactive was used for data acquisition in both positive and negative ion modes. The random forest package of R software was used for data screening and model building. Results: A total of 60 TB patients, including 30 ATB-DILI patients and 30 non-ATB-DILI subjects, were enrolled. There were no significant differences between the ATB-DILI and control groups in age, sex, smoking, drinking or body mass index (p > 0.05). Twenty-two differential metabolites were selected. According to KEGG pathway analysis, 9 significantly enriched metabolic pathways were found, and both drug metabolism-other enzymes and niacin and nicotinamide metabolic pathways were found in both positive and negative ion models. A total of 7 differential lipid molecules were identified between the two groups. Ferroptosis and biosynthesis of unsaturated fatty acids were involved in the occurrence of ATB-DILI. Random forest analysis showed that the model built with the top 30 important variables had an area under the ROC curve of 0.79 (0.65-0.93) for the training set and 0.79 (0.55-1.00) for the validation set. Conclusion: This study demonstrated that potential markers for the early prediction of ATB-DILI can be found through plasma metabolomics and lipidomics. The random forest model showed good clinical predictive value for ATB-DILI.PMID:36386176 | PMC:PMC9641415 | DOI:10.3389/fphar.2022.1044808

Front Pharmacol. 2022 Oct 31;13:1027931. doi: 10.3389/fphar.2022.1027931. eCollection 2022.ABSTRACTViscum album is a semi-parasitic plant used for over one hundred years in complementary cancer therapy. The main commercial drugs used in cancer patients' treatment are derived from the aqueous V. album extracts, whose cytotoxic potential is mostly attributed to the aqueous soluble antitumoral metabolites. On the counterpart, ethanol solvents must be used to obtain V. album mother tinctures. This methodology permits better solubilization of phenolic compounds, among others, which present antitumoral bioactivity. Recently, the metabolomics approach revealed the influence of the host tree on the V. album subspecies differentiation. To increase the scientific information about the chemical differences related to the host trees and to clarify the seasonal influences, in this study, the metabolome of 50 V. album mother tinctures from three subspecies (abietis, album, austriacum) and five host trees (Malus domestica, Quercus sp., Ulmus carpinifolia, Pinus sylvestris, Abies alba) was evaluated using summer and winter plant harvests. The in vitro cytotoxic activities were investigated in breast cancer cells (MDA-MB-231) and immortalized normal human keratinocytes (HaCaT). The summer V. album mother tinctures presented higher cytotoxic activity than winter ones. Among the summer samples, those prepared with V. album subsp. album were more cytotoxic than V. album subsp. abietis and subsp. V. album subsp. austriacum. The V. album harvested from Quercus petraea and Abies alba inhibited the key-glycolytic enzymes: hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK). This activity was related to a reduction in glucose uptake and lactate production, which were host-tree-time-dose-dependent. The untargeted metabolomic approach was able to discriminate the mother tinctures according to respective botanical classes and harvest season. A total of 188 metabolites were annotated under positive and negative modes. Fourteen compounds were responsible for the samples differentiation, and, to the best of our knowledge, eight were described in the Viscum album species for the first time. Our study shows the interruption of the Warburg effect as a novel antitumoral mechanism triggered by V. album mother tinctures, which is related to their metabolite profile. These results bring scientific evidence that encourages the use of V. album mother tinctures as a natural product for cancer therapy.PMID:36386174 | PMC:PMC9662615 | DOI:10.3389/fphar.2022.1027931

Front Pharmacol. 2022 Oct 31;13:1045843. doi: 10.3389/fphar.2022.1045843. eCollection 2022.ABSTRACTInter- and intrapatient variability of tacrolimus exposure is a vital prognostic risk factor for the clinical outcome of liver transplantation. New factors or biomarkers characterizing tacrolimus disposition is essential for optimal dose prediction in recipients of liver transplant. The aim of the study was to identify potential plasma metabolites associated with the dose-adjusted trough concentration of tacrolimus in liver transplant recipients by using a global metabolomic approach. A total of 693 plasma samples were collected from 137 liver transplant recipients receiving tacrolimus and regular therapeutic drug monitoring. Untargeted metabolomic analysis was performed by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry. Univariate and multivariate analyses with a mixed linear model were conducted, and the results showed that the dose-adjusted tacrolimus trough concentration was associated with 31 endogenous metabolites, including medium- and long-chain acylcarnitines such as stearoylcarnitine (β = 0.222, p = 0.001), microbiota-derived uremic retention solutes such as indolelactic acid (β = 0.194, p = 0.007), bile acids such as taurohyodeoxycholic acid (β = -0.056, p = 0.002), and steroid hormones such as testosterone (β = 0.099, p = 0.001). A multiple linear mixed model including 11 metabolites and clinical information was established with a suitable predictive performance (correlation coefficient based on fixed effects = 0.64 and correlation coefficient based on fixed and random effects = 0.78). These data demonstrated that microbiota-derived uremic retention solutes, bile acids, steroid hormones, and medium- and long-chain acylcarnitines were the main metabolites associated with the dose-adjusted trough concentration of tacrolimus in liver transplant recipients.PMID:36386159 | PMC:PMC9659571 | DOI:10.3389/fphar.2022.1045843

Front Pharmacol. 2022 Oct 26;13:1056614. doi: 10.3389/fphar.2022.1056614. eCollection 2022.ABSTRACTBackground: Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). B. Papyrifera (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. Methods: APP/PS1 transgenic mice were treated with different doses of BLWE. After 6 weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/β-catenin signaling pathway was detected by Western blotting. Results: After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin+/BrdU+ and NeuN+/BrdU+ cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also up-regulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3β and β-catenin protein while increased CyclinD1 protein expression. Conclusion: We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/β-catenin signaling pathway.PMID:36386124 | PMC:PMC9643563 | DOI:10.3389/fphar.2022.1056614

J Anal Methods Chem. 2022 Nov 4;2022:8026410. doi: 10.1155/2022/8026410. eCollection 2022.ABSTRACTDendrobium officinale (D. officinale) is a valuable traditional Chinese herbal medicine with high commercial value. In Chinese Pharmacopoeia (Ch.P., 2020 edition), the quality of D. officinale is mainly evaluated by its polysaccharide content. However, varying growth and production conditions, such as cultivation environment, origin, harvesting process, or processing methods, resulting in highly variable yields, quality, and composition. The aim of this study was to investigate whether the content of secondary metabolites in D. officinale from different origins is consistent with the polysaccharide content. The results showed that the polysaccharide content and pass rate were ranked as GX > AH > GZ > YN. Based on the nontargeted metabolomics approach, we searched for differential components in 22 different regions of D. officinale, including amides, bibenzyls, disaccharide, flavonoids, organic nitrogenous compounds, and phenolic glycosides. The overall expression was opposite to the polysaccharide, and the most expressed was YN, followed by GZ, AH, and GX. These results indicated that the current quality standard for evaluating the quality of D. officinale by polysaccharide content alone is imperfect, and small molecule compounds need to be included as quality markers.PMID:36385774 | PMC:PMC9652072 | DOI:10.1155/2022/8026410

Plant Biol (Stuttg). 2022 Nov 17. doi: 10.1111/plb.13489. Online ahead of print.ABSTRACTLow temperature limits the geographical distribution and yield of plants. Hormones play an important role in coordinating the growth and development of plants and their tolerance to low temperature. However, the mechanisms by which hormones affect plant resistance to extreme cold stress in the natural environment are still unclear. In this study, two winter wheat varieties with different cold resistances, Dn1 and J22, were used to conduct targeted plant hormone metabolome analysis on the tillering nodes of winter wheat at 5 °C, -10 °C and -25 °C using an LC-ESI-MS/MS system. We screened 39 hormones from 88 plant hormone metabolites and constructed a partial regulatory network of auxin, jasmonic acid and cytokinin. GO analysis and enrichment of KEGG pathways in differential metabolites showed that the "plant hormone signal transduction" pathway was the most typical. Our study showed that extreme low temperature increased the levels of most auxin, cytokinin and salicylic acid, and decreased the levels of jasmonic acid and abscisic acid, and the levels of auxin, jasmonic acid and cytokinin in Dn1 were greater than those in J22. These changes in hormone levels were associated with changes in gene expression in synthesis, catabolism, transport and signal transduction pathways. These results seem to be different from the previous hormone regulation mechanisms obtained mostly at 4 °C. Our results provide a basis for further understanding the molecular mechanisms by which plant endogenous hormones regulate plant freeze stress tolerance.PMID:36385725 | DOI:10.1111/plb.13489

J Sep Sci. 2022 Nov 17. doi: 10.1002/jssc.202200705. Online ahead of print.ABSTRACTMakyo-kanseki-to has been used for the treatment of pneumonia, becoming a basic formula for COVID-19. However, the chemical profile of Makyo-kanseki-to granule and its possible mechanism against acute lung injury from terminal metabolic regulation have been unclear. The aim of this study was to characterize the constituents in Makyo-kanseki-to granule and reveal the potential related mechanism of Makyo-kanseki-to granule treatment for acute lung injury using a rat model of lipopolysaccharide induced acute lung injury. Totally, 78 constituents were characterized based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Makyo-kanseki-to granule could alleviate acute lung injury through modulating rectal temperature, pulmonary edema, histopathology, processes of inflammatory and oxidative stress. 22 potential biomarkers in acute lung injury rats were identified by metabolomics based on ultra-performance liquid chromatography coupled with quadrupole exactive high field mass spectrometry. They were mainly involved in amino acids and glycerophospholipid metabolism, which were regulated by Makyo-kanseki-to granule. The present results not only increase the understanding on the chemical profile and molecular mechanism of Makyo-kanseki-to granule mediated protection against acute lung injury, but also provide experimental basis and new ideas for further development and clinical application of Makyo-kanseki-to granule. This article is protected by copyright. All rights reserved.PMID:36385590 | DOI:10.1002/jssc.202200705

Appl Microbiol Biotechnol. 2022 Nov 17. doi: 10.1007/s00253-022-12265-7. Online ahead of print.ABSTRACTAtherosclerosis (AS) is a major cause of death and morbidity worldwide. There is an increasing amount of evidence that the gut microbiota plays an important role in disorders associated with lipid metabolism, such as AS, and alterations in the composition of the gut microbiota and its metabolic potential have been identified as contributing factors in the development of AS. Recently, probiotics have attracted great interest for their excellent cholesterol-lowering ability, their capacity to improve vascular endothelial function, and their participation in the remodeling of the intestinal flora to prevent AS. The incidental findings of our other study suggest that probiotic Lactobacillus rhamnosus GG may be associated with slowing the progression of AS. Thus, we delivered strain GG into mice by oral feeding and found that strain GG could effectively inhibit AS plaque generation. We analyzed the differences in gut microbiota composition and the peripheral blood metabolome in mice after oral feeding of strain GG by 16S DNA sequencing and untargeted metabolomics, respectively. The results showed that strain GG changed the composition of the gut microbiota in mice fed a high-fat diet; elevated the abundance of beneficial bacteria, such as Bilophila and Alistipes, and decreased the abundance of harmful bacteria, such as Deltaproteobacteria. The results of enrichment analysis of the gut microbiota and the peripheral blood metabolome both indicated that the antiatherosclerotic effect of strain GG might be associated with the biosynthesis pathway of ketone bodies. In addition, strain GG attenuated endothelial injury and elevated peripheral blood ketone body content in mice but did not significantly affect low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) content. In conclusion, our study provides new evidence that strain GG slows the progression of AS, which may be associated with its improvement of the gut microbiome and peripheral blood metabolome, its ability to increase the abundance of beneficial bacteria, and its participation in unsaturated fatty acid and ketone body synthesis and degradation. KEY POINTS: • L. rhamnosus GG attenuated endothelial injury and atherosclerotic plaque formation • L. rhamnosus GG elevated the abundance of beneficial bacteria • L. rhamnosus GG elevated peripheral blood ketone body content in mice.PMID:36385568 | DOI:10.1007/s00253-022-12265-7

Nature. 2022 Nov 16. doi: 10.1038/s41586-022-05439-w. Online ahead of print.ABSTRACTAPOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.PMID:36385529 | DOI:10.1038/s41586-022-05439-w

Sci Rep. 2022 Nov 16;12(1):19716. doi: 10.1038/s41598-022-23977-1.ABSTRACTThe aim of the study was to compare the metabolomic synovial fluid (SF) profile of dogs affected by spontaneous osteoarthritis (OA) and supplemented with undenatured type II collagen (UC-II), with that of healthy control dogs. Client-owned dogs were enrolled in the study and randomized in two different groups, based on the presence/absence of OA (OA group and OA-free group). All dogs were clinically evaluated and underwent SF sampling for 1H-Nuclear Magnetic Resonance spectroscopy (1H-NMR) analysis at time of presentation. All dogs included in OA group were supplemented with UC-II orally administered for 30 days. After this period, they were reassessed (OA-T30). The differences in the 1H-NMR metabolic SFs profiles between groups (OA-free, OA-T0 and OA-T30) were studied. The multivariate statistical analysis performed on SFs under different conditions (OA-T0 vs OA-T30 SFs; OA-T0 vs OA-free SFs and OA-T30 vs OA-free SFs) gave models with excellent goodness of fit and predictive parameters, revealed by a marked separation between groups. β-Hydroxybutyrate was identified as a characteristic compound of osteoarthritic joints, showing the important role of fat metabolism during OA. The absence of β-hydroxybutyrate after UC-II supplementation suggests the supplement's effectiveness in rebalancing the metabolism inside the joint. The unexpectedly high level of lactate in the OA-free group suggests that lactate could not be considered a good marker for OA. These results prove that 1H-NMR-based metabolomic analysis is a valid tool to study and monitor OA and that UC-II improves clinical symptoms and the SF metabolic profile in OA dogs.PMID:36385297 | DOI:10.1038/s41598-022-23977-1

Cell Rep Med. 2022 Nov 15;3(11):100818. doi: 10.1016/j.xcrm.2022.100818.ABSTRACTAntibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSAs) are associated with a higher risk of AMR, not all patients with DSAs develop rejection, suggesting that the characteristics of alloantibodies determining their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we apply systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and FcγR-binding properties. Levels of afucosylated anti-A2 antibodies are elevated in seropositive patients, especially those with AMR, suggesting potential cytotoxicity via FcγRIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 drives potentiated binding to, slower dissociation from, and enhanced signaling through FcγRIII, a receptor widely expressed on innate effector cells, and greater cytotoxicity against HLA-A2+ cells mediated by natural killer (NK) cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and contribute to pathogenesis.PMID:36384101 | DOI:10.1016/j.xcrm.2022.100818

Cell Rep Med. 2022 Nov 15;3(11):100720. doi: 10.1016/j.xcrm.2022.100720.ABSTRACTAnti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL.PMID:36384092 | DOI:10.1016/j.xcrm.2022.100720

Braz Oral Res. 2022 Nov 11;36:e0128. doi: 10.1590/1807-3107bor-2022.vol36.0128. eCollection 2022.ABSTRACTThe aim of this study was to characterize the salivary metabolomic profile in adolescents with juvenile systemic lupus erythematosus (jSLE). A total of 24 adolescents with jSLE (15.92 ± 2.06 years) and 12 systemically healthy controls (15.25 ± 2.7 years) were included in the study. Participants underwent rheumatologic testing and periodontal examination, with the recording of plaque index (PI), probing depth (PD), clinical attachment level (CAL), and bleeding on probing index (BPI). Unstimulated whole saliva was collected from both groups and stored at -80 ºC. The salivary proton nuclear magnetic resonance (1H-NMR) spectra were acquired in a spectrometer operating at 500 MHz. Partial least squared discriminant analysis (PLS-DA) and orthogonal PLS-DA (O-PLS-DA) were used for statistical analysis. Mean CAL and PI were significantly increased in the group with jSLE (p < 0.01). Patients with jSLE presented a significantly different salivary metabolic profile (accuracy = 0.54; R2 = 0.86; Q2 = -0.293), significantly higher salivary levels of N-acetyl sugars, and significantly reduced levels of phenylalanine, glycine, taurine, hydroxybutyrate, and valerate compared with healthy controls (p < 0.05). It is suggested that the salivary metabolomic profile analyzed by 1H NMR in patients with jSLE presents a different fingerprint that the systemically healthy subjects. Integrating the variation of metabolites with the identification of the metabolic pathways involved seems to provide a better understanding of the influence of systemic disease on salivary metabolites.PMID:36383834 | DOI:10.1590/1807-3107bor-2022.vol36.0128

MAbs. 2022 Jan-Dec;14(1):2145929. doi: 10.1080/19420862.2022.2145929.ABSTRACTA relatively low clearance is one of the prominent favorable features of immunoglobulin G1-based therapeutic monoclonal antibodies (mAbs). Various studies have observed differential clearance of mAb glycoforms, including oligomannose glycoforms, which are considered a critical quality attribute because they show higher clearance than complex type glycoforms. Glycoform clearance, however, has not previously been studied after subcutaneous injection or in a porcine model system. Here, we performed glycoform-resolved pharmacokinetic (PK) analysis of two mAbs in Göttingen minipigs. We found glycoform effects on clearance to be largely the same for subcutaneous and intravenous injection and in line with observations in other species. Oligomannose glycoforms were cleared up to 25% faster and monoantennary glycoforms up to 8% faster than agalactosylated complex glycoforms. Sialylated glycoforms were cleared at approximately the same rate as fully galactosylated glycoforms. Importantly, we report here an impact of galactosylation on the PK of a mAb for the first time. Whether increased galactosylation led to slower or faster clearance seemed to depend on the overall glycosylation profile. When clearance of galactosylated glycoforms was slower, the mAb showed higher galactosylation in serum at maximum concentration after subcutaneous injection compared to both intravenous injection and the injected material. Whether this higher galactosylation after subcutaneous injection has consequences for therapeutic efficacy remains to be investigated. In conclusion, preferential clearance of antibody glycoforms can be simulated in the minipig model with intravenous as well as subcutaneous injections. Furthermore, we observed a glycoform bias in the absorption from skin into circulation after subcutaneous injection based on galactosylation.Abbreviations: AUC - area under the curve; CL/F - apparent clearance as a function of bioavailability following SC administration; Cmax - maximum serum concentration; CQA critical quality attribute; FcγR - Fc gamma receptor; IgG - immunoglobulin G; IV - intravenous; LC-MS - liquid chromatography - mass spectrometry; mAb - therapeutic monoclonal antibody; PK - pharmacokinetics; SC - subcutaneous; TMDD - target-mediated drug disposition.PMID:36383465 | DOI:10.1080/19420862.2022.2145929

J Agric Food Chem. 2022 Nov 16. doi: 10.1021/acs.jafc.2c05053. Online ahead of print.ABSTRACTHesperetin-7-O-glucoside (Hes-7-G) is a typical flavonoid monoglucoside, which can be generated from hesperidin with the removal of rhamnose by hydrolysis. Untargeted and targeted metabolomics together with 16S rRNA gene sequencing were employed to explore the exact absorption site of Hes-7-G and its beneficial effect in mice. Intestinal 1H nuclear magnetic resonance (NMR)-based metabolomics screening showed that Hes-7-G is mainly metabolized in the small intestine of mice, especially the ileum segment. Quantification analysis of bile acids (BAs) in the liver, intestinal tract, feces, and serum of mice suggests that Hes-7-G intake accelerates the processes of biosynthesis and excretion of BAs, thus promoting digestion and lowing hepatic cholesterol and triglyceride. 16S rRNA gene sequencing reveals that Hes-7-G significantly elevates the diversity of the gut microbiota in mice, especially those bacteria associated with BA secondary metabolism. These results demonstrated that long-term dietary Hes-7-G plays beneficial roles in health by modulating the gut bacteria and BA metabolism in mice.PMID:36383360 | DOI:10.1021/acs.jafc.2c05053

J Food Sci. 2022 Nov 16. doi: 10.1111/1750-3841.16376. Online ahead of print.ABSTRACTPerilla (Perilla frutescens, PF) is an annual labiaceae herb that can be used as vegetable, seasoner, and herb, which mainly includes red PF (P. frutescens var. crispa) and green PF (P. frutescens var. frutescens). Red and green Perilla is mainly used for medicine and food, respectively. In order to explore the differences between these two Perilla cultivars and the effects of origin on them, we studied the components of 130 Perilla samples from different origins by ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry combined with partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis. In this study, 57 potential compounds were analyzed, mainly including organic acids, flavonoids, terpenoids, and anthocyanins. In different varieties of Perilla, anthocyanins were found only in red PF. In addition, the content of four flavonoids, two organic acids, and one coumarin in red PF is much higher than that in green PF. Among the same variety of Perilla, the contents of three metabolites were higher in the north of China for red Perilla, while five metabolites were higher in the south of China for green Perilla. Overall, this research provided a basis for distinguishing different varieties and sources of Perilla through the differential metabolites of Perilla.PMID:36382855 | DOI:10.1111/1750-3841.16376