Metabolic Regulatory Mechanisms Research Articles

Normalized Brain Tissue-Level Evaluation of Volumetric Changes of Youth Athletes Participating in Collision Sports.

Observations of short-term changes in the neural health of youth athletes participating in collision sports (e.g., football and soccer) have highlighted a need to explore potential structural alterations in brain tissue volumes for these persons. Studies have shown biochemical, vascular, functional connectivity, and white matter diffusivity changes in the brain physiology of these athletes that are strongly correlated with repetitive head acceleration exposure. Here, research is presented that highlights regional anatomical volumetric measures that change longitudinally with accrued subconcussive trauma. A novel pipeline is introduced that provides simplified data analysis on standard-space template to quantify group-level longitudinal volumetric changes within these populations. For both sports, results highlight incremental relative regional volumetric changes in the subcortical cerebrospinal fluid that are strongly correlated with head exposure events greater than a 50-G threshold at the short-term post-season assessment. Moreover, longitudinal regional gray matter volumes are observed to decrease with time, only returning to baseline/pre-participation levels after sufficient (5–6 months) rest from collision-based exposure. These temporal structural volumetric alterations are significantly different from normal aging observed in sex- and age-matched controls participating in non-collision sports. Future work involves modeling repetitive head exposure thresholds with multi-modal image analysis and understanding the underlying physiological reason. A possible pathophysiological pathway is presented, highlighting the probable metabolic regulatory mechanisms. Continual participation in collision-based activities may represent a risk wherein recovery cannot occur. Even when present, the degree of the eventual recovery remains to be explored, but has strong implications for the well-being of collision-sport participants.

Tools, tactics and objectives to interrogate cellular roles of O-GlcNAc in disease.

The vast array of cell types of multicellular organisms must individually fine-tune their internal metabolism. One important metabolic and stress regulatory mechanism is the dynamic attachment/removal of glucose-derived sugar N-acetylglucosamine on proteins (O-GlcNAcylation). The number of proteins modified by O-GlcNAc is bewildering, with at least 7,000 sites in human cells. The outstanding challenge is determining how key O-GlcNAc sites regulate a target pathway amidst thousands of potential global sites. Innovative solutions are required to address this challenge in cell models and disease therapy. This Perspective shares critical suggestions for the O-GlcNAc field gleaned from the international O-GlcNAc community. Further, we summarize critical tools and tactics to enable newcomers to O-GlcNAc biology to drive innovation at the interface of metabolism and disease. The growing pace of O-GlcNAc research makes this a timely juncture to involve a wide array of scientists and new toolmakers to selectively approach the regulatory roles of O-GlcNAc in disease.

Comparative Metabolomics Reveals Two Metabolic Modules Affecting Seed Germination in Rice (Oryza sativa).

The process of seed germination is crucial not only for the completion of the plant life cycle but also for agricultural production and food chemistry; however, the underlying metabolic regulation mechanism involved in this process is still far from being clearly revealed. In this study, one indica variety (Zhenshan 97, with rapid germination) and one japonica variety (Nipponbare, with slow germination) in rice were used for in-depth analysis of the metabolome at different germination stages (0, 3, 6, 9, 12, 24, 36, and 48 h after imbibition, HAI) and exploration of key metabolites/metabolic pathways. In total, 380 annotated metabolites were analyzed by using a high-performance liquid chromatography (HPLC)-based targeted method combined with a nontargeted metabolic profiling method. By using bioinformatics and statistical methods, the dynamic changes in metabolites during germination in the two varieties were compared. Through correlation analysis, coefficient of variation analysis and differential accumulation analysis, 74 candidate metabolites that may be closely related to seed germination were finally screened. Among these candidates, 29 members belong to the ornithine–asparagine–polyamine module and the shikimic acid–tyrosine–tryptamine–phenylalanine–flavonoid module. As the core member of the second module, shikimic acid’s function in the promotion of seed germination was confirmed by exogenous treatment. These results told that nitrogen flow and antioxidation/defense responses are potentially crucial for germinating seeds and seedlings. It deepens our understanding of the metabolic regulation mechanism of seed germination and points out the direction for our future research.

Neuron-Specific Mechanisms Control the Mitochondrial Regulator PGC-1a

Dementia is an increasingly important public health problem with known vascular contributors. Respiratory function, measured by peak expiratory flow (PEF), may be a novel modifiable risk factor in reducing the risk of dementia along the vascular pathway. We investigated the association between PEF and incident dementia in older adults from the National Health and Aging Trends Study (NHATS). Using NHATS criteria, participants were categorized as having or not having probable incident dementia during NHATS Rounds 2-4, spanning three years. Of 3,622 participants with available PEF and covariate data, 543 (15.0%) had incident cases of dementia. Quartile of baseline PEF was analyzed as a predictor of incident dementia using logistic regression models, while controlling for several health and sociodemographic covariates. The fourth quartile of PEF had statistically significantly decreased odds of incident dementia when compared to the first PEF quartile (OR = 0.27; 95% CI [0.19, 0.40]). Significantly reduced odds of incident dementia were found when comparing the third and second PEF quartiles to the first PEF quartile, as well (OR = 0.35; 95% CI [0.26, 0.47] and OR = 0.62; 95% CI [0.48, 0.80], respectively). These relationships were dose-dependent so that increasing PEF quartile levels were more protective against incident dementia. PEF may be considered as an easily administered, low-cost measure of respiratory function and a possible screening tool for dementia risk. Improving PEF may reduce dementia risk through vascular mechanisms (e.g., increased blood circulation and brain oxygenation). Future research should explore these potential causal pathways between PEF and dementia.

Soybean-BioCro: a semi-mechanistic model of soybean growth

Abstract Soybean is a major global source of protein and oil. Understanding how soybean crops will respond to the changing climate and identifying the responsible molecular machinery are important for facilitating bioengineering and breeding to meet the growing global food demand. The BioCro family of crop models are semi-mechanistic models scaling from biochemistry to whole crop growth and yield. BioCro was previously parameterized and proved effective for the biomass crops Miscanthus, coppice willow and Brazilian sugarcane. Here, we present Soybean-BioCro, the first food crop to be parameterized for BioCro. Two new module sets were incorporated into the BioCro framework describing the rate of soybean development and carbon partitioning and senescence. The model was parameterized using field measurements collected over the 2002 and 2005 growing seasons at the open air [CO2] enrichment (SoyFACE) facility under ambient atmospheric [CO2]. We demonstrate that Soybean-BioCro successfully predicted how elevated [CO2] impacted field-grown soybean growth without a need for re-parameterization, by predicting soybean growth under elevated atmospheric [CO2] during the 2002 and 2005 growing seasons, and under both ambient and elevated [CO2] for the 2004 and 2006 growing seasons. Soybean-BioCro provides a useful foundational framework for incorporating additional primary and secondary metabolic processes or gene regulatory mechanisms that can further aid our understanding of how future soybean growth will be impacted by climate change.

Acetylation of glucosyltransferases regulates Streptococcus mutans biofilm formation and virulence.

Lysine acetylation is a frequently occurring post-translational modification (PTM), emerging as an important metabolic regulatory mechanism in prokaryotes. This process is achieved enzymatically by the protein acetyltransferase (KAT) to specifically transfer the acetyl group, or non-enzymatically by direct intermediates (acetyl phosphate or acetyl-CoA). Although lysine acetylation modification of glucosyltransferases (Gtfs), the important virulence factor in Streptococcus mutans, was reported in our previous study, the KAT has not been identified. Here, we believe that the KAT ActG can acetylate Gtfs in the enzymatic mechanism. By overexpressing 15 KATs in S. mutans, the synthesized water-insoluble extracellular polysaccharides (EPS) and biofilm biomass were measured, and KAT (actG) was identified. The in-frame deletion mutant of actG was constructed to validate the function of actG. The results showed that actG could negatively regulate the water-insoluble EPS synthesis and biofilm formation. We used mass spectrometry (MS) to identify GtfB and GtfC as the possible substrates of ActG. This was also demonstrated by in vitro acetylation assays, indicating that ActG could increase the acetylation levels of GtfB and GtfC enzymatically and decrease their activities. We further found that the expression level of actG in part explained the virulence differences in clinically isolated strains. Moreover, overexpression of actG in S. mutans attenuated its cariogenicity in the rat caries model. Taken together, our study demonstrated that the KAT ActG could induce the acetylation of GtfB and GtfC enzymatically in S. mutans, providing insights into the function of lysine acetylation in bacterial virulence and pathogenicity.

An emerging simple and effective approach to increase the productivity of thraustochytrids microbial lipids by regulating glycolysis process and triacylglycerols\u2019 decomposition

BackgroundThe oleaginous microorganism Schizochytrium sp. is widely used in scientific research and commercial lipid production processes. However, low glucose-to-lipid conversion rate (GLCR) and low lipid productivity of Schizochytrium sp. restrict the feasibility of its use.ResultsOrlistat is a lipase inhibitor, which avoids triacylglycerols (TAGs) from hydrolysis by lipase. TAGs are the main storage forms of fatty acids in Schizochytrium sp. In this study, the usage of orlistat increased the GLCR by 21.88% in the middle stage of fermentation. Whereas the productivity of lipid increased 1.34 times reaching 0.73 g/L/h, the saturated fatty acid and polyunsaturated fatty acid yield increased from 21.2 and 39.1 to 34.9 and 48.5 g/L, respectively, indicating the advantages of using a lipase inhibitor in microbial lipids fermentation. Similarly, the system was also successful in Thraustochytrid Aurantiochytrium. The metabolic regulatory mechanisms stimulated by orlistat in Schizochytrium sp. were further investigated using transcriptomics and metabolomics. The results showed that orlistat redistributed carbon allocation and enhanced the energy supply when inhibiting the TAGs’ degradation pathway. Therefore, lipase in Schizochytrium sp. prefers to hydrolyze saturated fatty acid TAGs into the β-oxidation pathway.ConclusionsThis study provides a simple and effective approach to improve lipid production, and makes us understand the mechanism of lipid accumulation and decomposition in Schizochytrium sp., offering new guidance for the exploitation of oleaginous microorganisms.

Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism.

Liver fibrosis is a progressive liver damage condition caused by various factors and may progress toward liver cirrhosis, and even hepatocellular carcinoma. Many studies have found that the disfunction in metabolism could contribute to the development of liver fibrosis. Geniposide, derived from Gardenia jasminoides J. Ellis, has been demonstrated with therapeutic effects on liver fibrosis. However, the exact molecular mechanisms of such liver-protection remain largely unknown. The aim of this study was to explored the effect of geniposide on metabolic regulations in liver fibrosis. We used carbon tetrachloride (CCl4) to construct a mouse model of liver fibrosis and subsequently administered geniposide treatment. Therapeutic effects of geniposide on liver fibrosis were accessed through measuring the levels of hepatic enzymes in serum and the pathological changes in liver. We also investigated the effects of geniposide on inflammatory response, oxidative stress and apoptosis in liver. Furthermore, serum untargeted metabolomics were used to explore the metabolic regulatory mechanisms behind geniposide on liver fibrosis. Our results demonstrated that geniposide could reduce the levels of hepatic enzymes in serum and ameliorate the pathological changes in liver fibrosis mice. Geniposide enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased methane dicarboxylic aldehyde (MDA) levels in liver. Geniposide treatment also decreased the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-a) in liver tissue homogenate. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining demonstrated that geniposide could reduce the apoptosis of hepatocytes. Geniposide increased the protein expression of B-cell lymphoma-2 (Bcl-2) and downregulated the protein expression of Bcl-2 Associated X (Bax), cleaved-Caspase 3, and cleaved-Caspase 9. Serum untargeted metabolomics analysis demonstrated that geniposide treatment improved the metabolic disorders including glycerophospholipid metabolism, arginine and proline metabolism, and arachidonic acid (AA) metabolism. In conclusion, our study demonstrated the protective effects of geniposide on liver fibrosis. We found that geniposide could treat liver fibrosis by inhibiting oxidative stress, reducing inflammatory response and apoptosis in the liver, and modulating glycerophospholipid, and arginine, proline, and AA metabolism processes.

Insights Into Mechanism of the Naphthalene-Enhanced Biodegradation of Phenanthrene by Pseudomonas sp. SL-6 Based on Omics Analysis.

The existence of polycyclic aromatic hydrocarbons (PAHs) in contaminated environment is multifarious. At present, studies of metabolic regulation focus on the degradation process of single PAH. The global metabolic regulatory mechanisms of microorganisms facing coexisting PAHs are poorly understood, which is the major bottleneck for efficient bioremediation of PAHs pollution. Naphthalene (NAP) significantly enhanced the biodegradation of phenanthrene (PHE) by Pseudomonas sp. SL-6. To explore the underlying mechanism, isobaric tags for relative and absolute quantification (iTRAQ) labeled quantitative proteomics was used to characterize the differentially expressed proteins of SL-6 cultured with PHE or NAP + PHE as carbon source. Through joint analysis of proteome and genome, unique proteins were identified and quantified. The up-regulated proteins mainly concentrated in PAH catabolism, Transporters and Electron transfer carriers. In the process, the regulator NahR, activated by salicylate (intermediate of NAP-biodegradation), up-regulates degradation enzymes (NahABCDE and SalABCDEFGH), which enhances the biodegradation of PHE and accumulation of toxic intermediate–1-hydroxy-2-naphthoic acid (1H2Na); 1H2Na stimulates the expression of ABC transporter, which maintains intracellular physiological activity by excreting 1H2Na; the up-regulation of cytochrome C promotes the above process running smoothly. Salicylate works as a trigger that stimulates cell to respond globally. The conjecture was verified at transcriptional and metabolic levels. These new insights contribute to improving the overall understanding of PAHs-biodegradation processes under complex natural conditions, and promoting the application of microbial remediation technology for PAHs pollution.

Osthole alleviates pulmonary vascular remodeling by modulating microRNA-22–3p mediated lipid metabolic reprogramming

BackgroundPulmonary vascular remodeling is the key pathological feature of pulmonary arterial hypertension (PAH) characterized by a pattern of lipid-related insulin resistance(IR), hormonal derangements and metabolic reprogramming. Our previous studies have demonstrated osthole as natural coumarin compound derived from traditional Chinese medicine is a promising agent for the treatment of pulmonary vascular remodeling in PAH. PurposeThe present study sought to delineate lipid metabolic modulatory mechanism of osthole against pulmonary vascular remodeling by employing an interdisciplinary strategy. MethodsRat model with PAH induced with MCT and PASMCs proliferation model induced with PDGF-BB were established in this study. Serum and lung tissues were used to lipid-related IR, hormone related indexes, pulmonary vascular remodeling analysis. Then, lipid metabolic gene, key enzymes, metabolites and cell proliferation indexes were examined to investigate metabolic regulatory mechanism in vivo and vitro model of PAH. ResultsOsthole significantly showed improvement of lipid-related IR and hormone dysregulation in rats with PAH evidenced by elevating testosterone, androgen receptor and cyclic guanosine monophosphate (cGMP), inhibiting phosphodiesterase-5(PDE-5), modulating lipid-related IR indexes total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG)/HDL-C ratio. Additionally, osthole limited key metabolic gene and enzymes to inhibit accumulation of decadienyl-l-carnitine in lipid metabolism, thus to promote oxidative phosphorylation and ATP production through inhibition of miRNA-22–3p, fatty acid translocase (CD36), fatty acid synthase (FAS), phospholipase A2 (PLA2), carnitine palmitoyltransferase 1A (CPT1A), hexokinase 2 (HK2), activation of metabolic switch isocitrate dehydrogenase 3α (IDH3α), NADH dehydrogenase 1 (ND1). We found for the first time miRNA-22–3p modulated PASMCs proliferation and vascular remodeling by regulating lipid metabolism reprogramming. Those modifications uncovered therapeutic mechanism of osthole against pulmonary vascular remodeling. ConclusionOur findings revealed the function of miRNA-22–3p in PASMCs and demonstrated a novel mechanism that miRNA-22–3p as a regulator can be targeted by osthole to greatly restore dysregulated lipid metabolism thus to alleviate pulmonary vascular remodeling in PAH, which provides novel insight into the potential therapeutic target for PAH, further highlights the development potential of osthole derived new drug against PAH.

An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.

To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology. We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.

Reprogramming the metabolism of Synechocystis PCC 6803 by regulating the plastoquinone biosynthesis

Cyanobacteria can utilize CO2 or even N2 to produce a variety of high value-added products efficiently. Plastoquinone (PQ) is an important electron carrier in both of the photosynthetic and respiratory electron transport chain. Although the content of PQ, as well as their redox state, have an important effect on physiology and metabolism, there are relatively few studies on the synthesis of PQ and its related metabolic regulation mechanism in photosynthetic microorganisms. In this study, the strategies of overexpression of Geranyl diphosphate: 4-hydroxybenzoate geranyltransferase (lepgt) and addition of 4-hydroxybenzoate (4-HB) as the quinone ring precursor were adopted to regulate the biosynthesis of PQ in Synechocystis PCC 6803. Combined with the analysis the photosystem activity, respiration rate and metabolic components, we found the changes of intracellular PQ reprogrammed the metabolism of Synechocystis PCC 6803. The results showed that the overexpression of lepgt reduced PQ content dramatically, by 22.18%. Interestingly, both of the photosynthesis and respiration rate were enhanced. In addition, the intracellular lipid and protein contents were significantly increased. Whereas, the addition of low concentrations of 4-HB enhanced the biosynthesis of PQ, and the intracellular PQ contents were increased by 14.76%–70.86% in different conditions. Addition of 4-HB can regulate the photosystem efficiency and respiration and reprogram the metabolism of Synechocystis PCC 6803 efficiently. In a word, regulating the PQ biosynthesis provided a novel idea for promoting the reprogramming the physiology and metabolism of Synechocystis.

An overview of branched-chain amino acid aminotransferases: functional differences between mitochondrial and cytosolic isozymes in yeast and human.

Branched-chain amino acid aminotransferase (BCAT) catalyzes bidirectional transamination in the cell between branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and branched-chain α-keto acids (BCKAs; α-ketoisovalerate, α-ketoisocaproate, and α-keto-β-methylvalerate). Eukaryotic cells contain two types of paralogous BCATs: mitochondrial BCAT (BCATm) and cytosolic BCAT (BCATc). Both isozymes have identical enzymatic functions, so they have long been considered to perform similar physiological functions in the cells. However, many studies have gradually revealed the differences in physiological functions and regulatory mechanisms between them. In this article, we present overviews of BCATm and BCATc in both yeast and human. We also introduce BCAT variants found natively or constructed artificially, which could have significant implications for research into the relationship between the primary structures and protein functions of BCATs. KEY POINTS: • BCAT catalyzes bidirectional transamination in the cell between BCAAs and BCKAs. • BCATm and BCATc are different in the metabolic roles and regulatory mechanisms. • BCAT variants offer insight into a relationship between the structure and function.

Metabolic and Transcriptomic Profiling of Lilium Leaves Infected With Botrytis elliptica Reveals Different Stages of Plant Defense Mechanisms.

Botrytis elliptica, the causal agent of gray mold disease, poses a major threat to commercial Lilium production, limiting its ornamental value and yield. The molecular and metabolic regulation mechanisms of Lilium's defense response to B. elliptica infection have not been completely elucidated. Here, we performed transcriptomic and metabolomic analyses of B. elliptica resistant Lilium oriental hybrid “Sorbonne” to understand the molecular basis of gray mold disease resistance in gray mold disease. A total of 115 differentially accumulated metabolites (DAMs) were detected by comparing the different temporal stages of pathogen infection. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed the differentially expressed genes (DEGs) and DAMs were enriched in the phenylpropanoid and flavonoid pathways at all stages of infection, demonstrating the prominence of these pathways in the defense response of “Sorbonne” to B. elliptica. Network analysis revealed high interconnectivity of the induced defense response. Furthermore, time-course analysis of the transcriptome and a weighted gene coexpression network analysis (WGCNA) led to the identification of a number of hub genes at different stages, revealing that jasmonic acid (JA), salicylic acid (SA), brassinolide (BR), and calcium ions (Ca2+) play a crucial role in the response of “Sorbonne” to fungal infection. Our work provides a comprehensive perspective on the defense response of Lilium to B. elliptica infection, along with a potential transcriptional regulatory network underlying the defense response, thereby offering gene candidates for resistance breeding and metabolic engineering of Lilium.

Comprehensive mining of storage oil related genes in developing seed of Abelmoschus esculentus

Okra (Abelmoschus esculentus), famous for its desired nutritional and medicinal values, could accumulate approximately 20% (w/w) seed oil dominated with unsaturated fatty acids (UFAs). However, the mechanism of oil biosynthesis and metabolic regulation in its seeds remains poorly understood. Here, storage oil profiles and transcriptome of okra seeds at different developmental stages were analyzed. Seed oil accumulated at a high rate during 21 to 28 days after flowering (DAF). Total of 136.6 million clean reads were obtained and 109,171 unigenes were assembled from the seed transcriptome. Differentially expressed genes among three developing stages of seeds were functionally annotated into the storage lipid metabolism pathway. Comparative analysis was performed for structural genes and transcription factor genes that participate in fatty acid biosynthesis, triacylglycerol assembly, oil body formation, and triacylglycerol degradation. A complex regulating network was built accordingly. Additionally, expressions of 12 key functional genes responsible for okra oil accumulation were examined by quantitative real-time PCR (qRT-PCR), demonstrating that RNA-sequencing data were reliable. This study will facilitate further investigation of molecular mechanism responsible for unsaturated fatty acid biosynthesis and oil accumulation in plant seed, providing valued reference for creating new okra varieties with better lipid composition and high oil yield.

Pithecellobium clypearia: Amelioration Effect on Imiquimod-Induced Psoriasis in Mice Based on a Tissue Metabonomic Analysis.

Pithecellobium clypearia Benth. (accepted name: Archidendron clypearia (Jack) I.C.Nielsen; Mimosaceae), a popular traditional Chinese medicine, has a significant anti-inflammatory effect. The crude water extract of the aerial part of P. clypearia has been clinically applied to treat upper respiratory tract infections, acute gastroenteritis, laryngitis, and pharyngitis. However, the therapeutic mechanism of ethanol fraction of water extract (ESW) of P. clypearia to treat psoriasis should be complemented. The aim of our research was to clarify the protective effects of ESW from P. clypearia against psoriasis-like skin inflammation induced by imiquimod (IMQ) in mice with efficacy indexes and target tissue (spleen and serum) metabolomics. The ingredient of ESW was analyzed by ultrahigh-performance liquid chromatography combined with tandem mass spectrometry (UHPLC-MS/MS) method. The imiquimod-induced psoriatic mouse model was employed to investigate the effect of ESW against psoriasis, where the treatment method was implemented for 6 days both topically (Gel at 5%) and orally (at 2.4 g/kg p.o.). Traditional pharmacodynamic indicators (phenotypic characteristics, psoriasis area and severity index (PASI) score, H&E staining, immunohistochemical staining, the thickness of epidermis, body weight change, and spleen index) were conducted to appraise the efficacy of ESW. Furthermore, a gas chromatography-mass spectrometer (GC-MS) coupled with multivariate analysis was integrated and applied to obtain serum and spleen metabolic profiles for clarifying metabolic regulatory mechanisms of ESW. The current study illustrated that ESW is composed mainly of gallic acid, ethyl gallate, quercitin, 7-O-galloyltricetiflavan, quercetin, and myricetin by UHPLC-MS/MS analysis. ESW could distinctly improve IMQ-induced psoriasis in mouse through reducing PASI score, alleviating tissue damage, restoring spleen index, and inhibiting proliferating cell nuclear antigen (PCNA) expression in psoriasis-like skin tissue. From the metabolomics study, 23 markers with significant changes are involved in eight main pathways in spleen and serum samples, including linoleic acid metabolism and glycine, serine, and threonine metabolism. The current study showed that ESW had obvious antipsoriasis effects on IMQ-induced psoriasis in mice, which might be attributed to regulating the dysfunction of differential biomarkers and related pathways. In summary, ESW of P. clypearia showed a favourable therapeutic effect on IMQ-induced psoriasis, and metabolomics provided insights into the mechanisms of ESW to the treatment of psoriasis.

2-Deoxy-D-glucose Alleviates Collagen-Induced Arthritis of Rats and Is Accompanied by Metabolic Regulation of the Spleen and Liver.

Rheumatoid arthritis (RA) is significantly associated with glycolysis. This study used 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, to treat rats with collagen-induced arthritis (CIA) and investigate the metabolic regulatory mechanism of glycolysis in the disease. 2-DG significantly alleviated CIA. Metabolomics and transcriptomics, as well as their integrative analysis, detected significant changes in the pathways of bile secretion, cholesterol and linoleic acid metabolism in the plasma, liver and spleen during the CIA process and the opposite changes following 2-DG treatment, whereas the expression of the genes regulating these metabolic pathways were changed only in the spleen. In the rat liver, levels of (S)-5-diphosphomevalonic acid in the terpenoid backbone biosynthesis pathway were significantly decreased during CIA progression and increased following 2-DG treatment, and levels of taurochenodeoxycholic acid in the pentose and glucuronate interconversions pathway showed the opposite results. In the spleen, levels of 3-methoxy-4-hydroxyphenylglycol glucuronide in bile secretion and 12(S)-leukotriene B4 in arachidonic acid metabolism were significantly decreased during CIA progression and increased following 2-DG treatment. The changes in the gene-metabolite network of bile secretion in the spleen correlated with a decreased plasma L-acetylcarnitine level in CIA rats and an increase following 2-DG treatment. Our analysis suggests the involvement of spleen and liver metabolism in CIA under the control of glycolysis.

The Effects of Glucagon-Like Peptide Type 1 (GLP-1) and its Analogues in Adipose Tissue: Is there a way to Thermogenesis?

Obesity is a global problem and the most common metabolic disorder leading to many associated diseases, such as arterial hypertension, ischemic heart disease, type 2 diabetes, certain types of cancer, impaired lipid and uric acid metabolism. The prevalence of obesity has risen globally in the past four decades in both children and adults, and it accounts for the rapid increase in the prevalence of diabetes. Currently, the study of thermogenic tissues, brown and beige adipose tissues, is of extreme value from the point of view of therapeutic potential for obesity and its associated diseases. An analogue of the glucagon-like peptide-1 (GLP-1) liraglutide, used in the treatment of type 2 diabetes, has been proven to have a positive effect on weight loss through appetite suppression. However, this mechanism of weight loss is not the only one involved. This article discusses the main molecular and cellular mechanisms of adipogenesis, as well as the effect of GLP-1 and its analogues, in particular liraglutide on this process through various transcription factors, signaling pathways, and hormones, including brown and beige adipose tissue. Also, the twincretins have had a positive effect on insulin resistance and fat beiging activation. The results of numerous studies have helped us to better understand the peripheral mechanisms of lipid metabolism regulation, and have demonstrated the effectiveness of GLP-1 analogues for the treatment of diabetes and obesity.

Comprehensive analysis of metabolism-related lncRNAs related to the progression and prognosis in osteosarcoma from TCGA

BackgroundOsteosarcoma is one of the most common malignant neoplasms in children and adolescents. Studies have shown that metabolism-related pathways are vital for the development and metastasis of osteosarcoma. Long non-coding RNA (lncRNA) plays a key role in the occurrence and progression of cancer in a variety of ways. However, the detailed molecular mechanisms of metabolism-related lncRNA in osteosarcoma remain to be deeply elucidated.MethodsIn this study, all metabolism-related mRNAs and lncRNAs in osteosarcoma were extracted and identified based on transcriptomic data from the TCGA database. Usingsurvival analysis, univariate and multivariate independent prognostic analysis, gene set enrichment analysis, and nomogram, a prognostic signature with metabolic lncRNAs as prognostic factors was constructed.ResultsNine prognostic factors included lncRNA AC009779.2, lncRNA AL591895.1, lncRNA AC026271.3, lncRNA LPP-AS2, lncRNA LINC01857, lncRNA AP005264.1, lncRNA LINC02454, lncRNA AL133338.1, and lncRNA AC135178.5, respectively. Survival analysis indicated that alterations of specific lncRNA expression were strongly correlated with poor prognosis in osteosarcoma. Univariate and multivariate independent prognostic analysis showed that the prognostic signature had a good independent predictive ability for patient survival. The results of GSEA suggested that these predictors may be involved in the metabolism of certain substances or energy in cancer. The nomogram was further drawn for clinical guidance and assistance in clinical decision-making.ConclusionsThis study identified multiple metabolism-related lncRNAs, which may be novel therapeutic targets for osteosarcoma, and contributed to better explore the specific metabolic regulatory mechanisms of lncRNA in osteosarcoma.

Oral, Tongue-Coating Microbiota, and Metabolic Disorders: A Novel Area of Interactive Research.

Interactions between colonizing microbiota and the host have been fully confirmed, among which the tongue-coating microbiota have a moderate rate of renewal and disease sensitivity and are easily obtained, making them an ideal research subject. Oral microbiota disorders are related to diabetes, obesity, cardiovascular disease, cancer, and other systemic diseases. As an important part of the oral cavity, tongue-coating microbiota can promote gastritis and digestive system tumors, affecting the occurrence and development of multiple chronic diseases. Common risk factors include diet, age, and immune status, among others. Metabolic regulatory mechanisms may be similar between the tongue and gut microbiota. Tongue-coating microbiota can be transferred to the respiratory or digestive tract and create a new balance with local microorganisms, together with the host epithelial cells forming a biological barrier. This barrier is involved in the production and circulation of nitric oxide (NO) and the function of taste receptors, forming the oral-gut-brain axis (similar to the gut-brain axis). At present, the disease model and mechanism of tongue-coating microbiota affecting metabolism have not been widely studied, but they have tremendous potential.