Regulation Of Amino Acid Metabolism Research Articles

Vitamin C Alleviates the Negative Effects of Heat Stress on Reproductive Processes by Regulating Amino Acid Metabolism in Granulosa Cells.

Heat stress-induced biochemical alterations in ovarian follicles compromise the function of granulosa cells (GCs) and the developmental competence of oocytes. Summer heat stress can have a far-reaching negative impact on overall fertility and reproductive success. Together with the heat stress, the rise of assisted reproductive technologies (ART), potential confounding hazards of in vitro handling and the absence of systemic body support in ART makes it imperative to study the heat stress ameliorative effects of vitamin C under in vitro conditions. Using in vitro heat stress treatment of 43 °C for two hours in bovine GCs, we studied the effects of vitamin C on cell growth, oxidative stress, apoptosis and cell cycle progression together with a comprehensive metabolomics profiling. This study investigates the molecular milieu underlying the vitamin C (VC)-led alleviation of heat-related disruptions to metabolic processes in bovine GCs. The supplementation of VC ameliorated the detrimental effects of heat stress by reducing oxidative stress and apoptosis while restoring cell proliferation. Normal cell function restoration in treated GCs was demonstrated through the finding of significantly high levels of progesterone. We observed a shift in the metabolome from biosynthesis to catabolism, mostly dominated by the metabolism of amino acids (decreased tryptophan, methionine and tyrosine) and the active TCA cycle through increased Succinic acid. The Glutathione and tryptophan metabolism were important in ameliorating the inflammation and metabolism nexus under heat stress. Two significant enzymes were identified, namely tryptophan 2,3-dioxygenase (TDO2) and mitochondrial phenylalanyl-tRNA synthetase (FARS2). Furthermore, our findings provide insight into the significance of B-complex vitamins in the context of heat stress during VC supplementation. This study underscores the importance of VC supplementation in heat stress and designates multiple metabolic intervention faucets in the context of ameliorating heat stress and enhancing reproductive efficiency.

Exploring the molecular mechanisms of Lrp/AsnC-type transcription regulator DecR, an L-cysteine-responsive feast/famine regulatory protein

The Lrp/AsnC family of transcriptional regulators is commonly found in prokaryotes and is associated with the regulation of amino acid metabolism. However, it remains unclear how the L-cysteine-responsive Lrp/AsnC family regulator perceives and responds to L-cysteine. Here, we try to elucidate the molecular mechanism of the L-cysteine-responsive transcriptional regulator. Through 5′RACE and EMSA, we discovered a 15 bp incompletely complementary pair palindromic sequence essential for DecR binding, which differed slightly from the binding sequence of other Lrp/AsnC transcription regulators. Using alanine scanning, we identified the L-cysteine binding site on DecR and found that different Lrp/AsnC regulators adjust their binding pocket's side-chain residues to accommodate their specific effector. MD simulations were then conducted to explore how ligand binding influences the allosteric behavior of the protein. PCA and in silico docking revealed that ligand binding induced perturbations in the linker region, triggering conformational alterations and leading to the relocalization of the DNA-binding domains, enabling the embedding of the DNA-binding region of DecR into the DNA molecule, thereby enhancing DNA-binding affinity. Our findings can broaden the understanding of the recognition and regulatory mechanisms of the Lrp/AsnC-type transcription factors, providing a theoretical basis for further investigating the molecular mechanisms of other transcription factors.

Trehalose enhances the resistance of Lactiplantibacillus plantarum LIP-1 to spray- and freeze-drying treatments by regulating amino acid metabolism

The effect of adding trehalose in the culture medium on Lactiplantibacillus plantarum LIP-1 was investigated during spray- and freeze-drying. Although previous studies reported that the enhancement of bacterial resistance is due to intracellular trehalose accumulation, our study revealed that it was related to trehalose metabolism by the strain, and not accumulation. The underlying mechanisms were mainly related to the activation of l-glutamic acid and cysteine metabolic pathways during trehalose metabolism. First, murL, murD, and vanY in the l-glutamic acid metabolic pathway were significantly upregulated, increasing peptidoglycan synthesis and thus improving the cell wall integrity during drying process. Second, gshA in the cysteine metabolic pathway was upregulated, increasing intracellular glutathione content, enhancing antioxidant capacity, and thereby reducing the degree of cell membrane damage during drying process. Third, alkaline substances produced during l-glutamic acid and cysteine metabolisms increased the intracellular pH and reduced the degree of DNA damage caused by acid stress.

Wnt/β-catenin signaling regulates amino acid metabolism through the suppression of CEBPA and FOXA1 in liver cancer cells

Deregulation of the Wnt/β-catenin pathway is associated with the development of human cancer including colorectal and liver cancer. Although we previously showed that histidine ammonia lyase (HAL) was transcriptionally reduced by the β-catenin/TCF complex in liver cancer cells, the mechanism(s) of its down-regulation by the complex remain to be clarified. In this study, we search for the transcription factor(s) regulating HAL, and identify CEBPA and FOXA1, two factors whose expression is suppressed by the knockdown of β-catenin or TCF7L2. In addition, RNA-seq analysis coupled with genome-wide mapping of CEBPA- and FOXA1-binding regions reveals that these two factors also increase the expression of arginase 1 (ARG1) that catalyzes the hydrolysis of arginine. Metabolome analysis discloses that activated Wnt signaling augments intracellular concentrations of histidine and arginine, and that the signal also increases the level of lactic acid suggesting the induction of the Warburg effect in liver cancer cells. Further analysis reveals that the levels of metabolites of the urea cycle and genes coding its related enzymes are also modulated by the Wnt signaling. These findings shed light on the altered cellular metabolism in the liver by the Wnt/β-catenin pathway through the suppression of liver-enriched transcription factors including CEBPA and FOXA1.

Reconstruction the feedback regulation of amino acid metabolism to develop a non-auxotrophic l-threonine producing Corynebacterium glutamicum

l-Threonine is an important feed additive with the third largest market size among the amino acids produced by microbial fermentation. The GRAS (generally regarded as safe) industrial workhorse Corynebacterium glutamicum is an attractive chassis for l-threonine production. However, the present l-threonine production in C. glutamicum cannot meet the requirement of industrialization due to the relatively low production level of l-threonine and the accumulation of large amounts of by-products (such as l-lysine, l-isoleucine, and glycine). Herein, to enhance the l-threonine biosynthesis in C. glutamicum, releasing the aspartate kinase (LysC) and homoserine dehydrogenase (Hom) from feedback inhibition by l-lysine and l-threonine, respectively, and overexpressing four flux-control genes were performed. Next, to reduce the formation of by-products l-lysine and l-isoleucine without the cause of an auxotrophic phenotype, the feedback regulation of dihydrodipicolinate synthase (DapA) and threonine dehydratase (IlvA) was strengthened by replacing the native enzymes with heterologous analogues with more sensitive feedback inhibition by l-lysine and l-isoleucine, respectively. The resulting strain maintained the capability of synthesizing enough amounts of l-lysine and l-isoleucine for cell biomass formation but exhibited almost no extracellular accumulation of these two amino acids. To further enhance l-threonine production and reduce the by-product glycine, l-threonine exporter and homoserine kinase were overexpressed. Finally, the rationally engineered non-auxotrophic strain ZcglT9 produced 67.63 g/L (17.2% higher) l-threonine with a productivity of 1.20 g/L/h (108.0% higher) in fed-batch fermentation, along with significantly reduced by-product accumulation, representing the record for l-threonine production in C. glutamicum. In this study, we developed a strategy of reconstructing the feedback regulation of amino acid metabolism and successfully applied this strategy to de novo construct a non-auxotrophic l-threonine producing C. glutamicum. The main end by-products including l-lysine, l-isoleucine, and glycine were almost eliminated in fed-batch fermentation of the engineered C. glutamicum strain. This strategy can also be used for engineering producing strains for other amino acids and derivatives.

4-phenylbutyric acid improves sepsis-induced cardiac dysfunction by modulating amino acid metabolism and lipid metabolism via Comt/Ptgs2/Ppara

IntroductionCardiac dysfunction after sepsis the most common and severe sepsis-related organ failure. The severity of cardiac damage in sepsis patients was positively associated to mortality. It is important to look for drugs targeting sepsis-induced cardiac damage. Our previous studies found that 4-phenylbutyric acid (PBA) was beneficial to septic shock by improving cardiovascular function and survival, while the specific mechanism is unclear.ObjectivesWe aimed to explore the specific mechanism and PBA for protecting cardiac function in sepsis.MethodsThe cecal ligation and puncture-induced septic shock models were used to observe the therapeutic effects of PBA on myocardial contractility and the serum levels of cardiac troponin-T. The mechanisms of PBA against sepsis were explored by metabolomics and network pharmacology.ResultsThe results showed that PBA alleviated the sepsis-induced cardiac damage. The metabolomics results showed that there were 28 metabolites involving in the therapeutic effects of PBA against sepsis. According to network pharmacology, 11 hub genes were found that were involved in lipid metabolism and amino acid transport following PBA treatment. The further integrated analysis focused on 7 key targets, including Comt, Slc6a4, Maoa, Ppara, Pparg, Ptgs2 and Trpv1, as well as their core metabolites and pathways. In an in vitro assay, PBA effectively inhibited sepsis-induced reductions in Comt, Ptgs2 and Ppara after sepsis.ConclusionsPBA protects sepsis-induced cardiac injury by targeting Comt/Ptgs2/Ppara, which regulates amino acid metabolism and lipid metabolism. The study reveals the complicated mechanisms of PBA against sepsis.

Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with Erwinia-derived asparaginase (also called crisantaspase). This led us to hypothesize that AML cells initiate the de novo serine biosynthesis pathway in response to crisantaspase treatment and that inhibiting this pathway in combination with crisantaspase would enhance AML cell death. Here we report that in AML cell lines, treatment with the clinically available crisantaspase, Rylaze, upregulates the serine biosynthesis enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) through activation of the Amino Acid Response (AAR) pathway, a cellular stress response mechanism that regulates amino acid metabolism and protein synthesis under conditions of nutrient limitation. Inhibition of serine biosynthesis through CRISPR-Cas9-mediated knockout of PHGDH resulted in a ~250-fold reduction in the half-maximal inhibitory concentration (IC50) for Rylaze, indicating heightened sensitivity to crisantaspase therapy. Treatment of AML cells with a combination of Rylaze and a small molecule inhibitor of PHGDH (BI4916) revealed synergistic anti-proliferative effects in both cell lines and primary AML patient samples. Rylaze-BI4916 treatment in AML cell lines led to the inhibition of cap-dependent mRNA translation and protein synthesis, as well as a marked decrease in intracellular glutathione levels, a critical cellular antioxidant. Collectively, our results highlight the clinical potential of targeting serine biosynthesis in combination with crisantaspase as a novel therapeutic strategy for AML.

The Water Extract of Rhubarb Prevents Ischemic Stroke by Regulating Gut Bacteria and Metabolic Pathways.

Rhubarb (RR), Chinese name Dahuang, is commonly used in the treatment of ischemic stroke (IS). However, its potential mechanism is not fully elucidated. This study intended to verify the effect of RR on IS and investigate the possible mechanism of RR in preventing IS. IS in male rats was induced by embolic middle cerebral artery occlusion (MCAO) surgery, and drug administration was applied half an hour before surgery. RR dramatically decreased the neurological deficit scores, the cerebral infarct volume, and the cerebral edema rate, and improved the regional cerebral blood flow (rCBF) and histopathological changes in the brain of MCAO rats. The 16S rRNA analysis showed the harmful microbes such as Fournierella and Bilophila were decreased, and the beneficial microbes such as Enterorhabdus, Defluviitaleaceae, Christensenellaceae, and Lachnospira were significantly increased, after RR pretreatment. 1H-nuclear magnetic resonance (1H-NMR) was used to detect serum metabolomics, and RR treatment significantly changed the levels of metabolites such as isoleucine, valine, N6-acetyllysine, methionine, 3-aminoisobutyric acid, N, N-dimethylglycine, propylene glycol, trimethylamine N-oxide, myo-inositol, choline, betaine, lactate, glucose, and lipid, and the enrichment analysis of differential metabolites showed that RR may participate in the regulation of amino acid metabolism and energy metabolism. RR exerts the role of anti-IS via regulating gut bacteria and metabolic pathways.

The Protective Effects of L-Theanine against Epigallocatechin Gallate-Induced Acute Liver Injury in Mice.

Epigallocatechin-3-gallate (EGCG) is a main bioactive constituent in green tea. Being a redox-active polyphenol, high-dose EGCG exhibits pro-oxidative activity and could cause liver injury. L-theanine is a unique non-protein amino acid in green tea and could provide liver-protective effects. The purpose of this study was to investigate the hepatoprotective effects of L-theanine on EGCG-induced liver injury and the underlying mechanisms. A total of 300 mg/kg L-theanine was administrated to ICR mice for 7 days. Then, the acute liver injury model was established through intragastric administration of 1000 mg/kg EGCG. Pretreatment with L-theanine significantly alleviated the oxidative stress and inflammatory response caused by high-dose EGCG through modulation of Nrf2 signaling and glutathione homeostasis. Furthermore, metabolomic results revealed that L-theanine protects mice from EGCG-induced liver injury mainly through the regulation of amino acid metabolism, especially tryptophan metabolism. These findings could provide valuable insights into the potential therapeutic applications of L-theanine and highlight the importance of the interactions between dietary components.

Identification of osteogenic differentiation-related miRNA-mRNA regulatory network of human periodontal ligament stem cells.

This study aimed to investigate the hub genes and miRNA-mRNA regulatory network around periodontal ligament stem cells (PDLSC) for osteogenic differentiation through bioinformatic analysis. The dataset with osteogenic differentiation of human PDLSC was downloaded from the GEO database. The Weighted gene coexpression network analysis (WGCNA) was performed to identify key modules and hub genes. In addition, differentially expressed genes (DEGs) analysis was conducted with limma. The functional enrichment of differentially expressed hub genes was implemented with KEGG and GSEA analysis. The targeted genes of differentially expressed miRNA were predicted based on miRWalk database. The miRNA-mRNA interaction network of osteogenic differentiation of PDLSC was constructed and visualized. The WGNCA results showed that the light-cyan module was positively correlated with osteogenic differentiation (r=0.98, P<0.05). A total of 3125 hub genes and 1426 differentially expressed hub genes were detected in OG group. Innate immune-related signaling pathways and metabolic pathways were involved in the osteogenic differentiation. In addition, total of 2 upregulated miRNAs with 63 targeted DEGs and 6 downregulated miRNAs with 214 targeted DEGs were detected, which contributed to osteogenic differentiation by regulating amino acid metabolism signaling pathway. We identified hub genes and miRNA-mRNA regulatory network contributing to osteogenic differentiation of human PDLSC, which will provide novel strategy for periodontal disease therapy.

Activating transcription factor 4: a regulator of stress response in human cancers.

Activating transcription factor 4 (ATF4) is an adaptive response regulator of metabolic and oxidative homeostasis. In response to cellular stress, ATF4 is activated and functions as a regulator to promote cell adaptation for survival. As a transcriptional regulator, ATF4 also widely participates in the regulation of amino acid metabolism, autophagy, redox homeostasis and endoplasmic reticulum stress. Moreover, ATF4 is associated with the initiation and progression of glioblastoma, hepatocellular carcinoma, colorectal cancer, gastric cancer, breast cancer, prostate cancer and lung cancer. This review primarily aims to elucidate the functions of ATF4 and its role in multiple cancer contexts. This review proposes potential therapeutic targets for clinical intervention.

Transmembrane protein 176B regulates amino acid metabolism through the PI3K-Akt-mTOR signaling pathway and promotes gastric cancer progression

BackgroundThe present study aimed to investigate the expression level, biological function, and underlying mechanism of transmembrane protein 176B (TMEM176B) in gastric cancer (GC).MethodsTMEM176B expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). The function of TMEM176B was determined by various in vitro assays including colony formation, 5-ethynyl-2ʹ-deoxyuridine (EdU), Transwell, and flow cytometry. Bioinformatics techniques were then used to elucidate the signaling pathways associated with TMEM176B activity. Tumor formation experiments were conducted on nude mice for in vivo validation of the preceding findings. TMEM176B expression was cross-referenced to clinicopathological parameters and survival outcomes.ResultsIt was observed that TMEM176B was overexpressed in GC cells and tissues. Targeted TMEM176B abrogation inhibited colony formation, proliferation, migration, and invasion but promoted apoptosis in GC cell lines while TMEM176B overexpression had the opposite effects. Subsequent experimental validation disclosed an association between TMEM176B and the phosphatidylinositol 3-carboxykinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling axis. Moreover, TMEM176B affects GC cancer progression by regulating asparagine synthetase (ASNS). The in vivo assays confirmed that TMEM176B is oncogenic and the clinical data revealed a connection between TMEM176B expression and the clinicopathological determinants of GC.ConclusionThe foregoing results suggest that TMEM176B significantly promotes the development of gastric cancer and is an independent prognostic factor of it.

Supplementation with Astragalus Root Powder Promotes Rumen Microbiota Density and Metabolome Interactions in Lambs.

The gut microbiota is highly symbiotic with the host, and the microbiota and its metabolites are essential for regulating host health and physiological functions. Astragalus, as a feed additive, can improve animal immunity. However, the effects of Astragalus root powder on the rumen microbiota and their metabolites in lambs are not apparent. In this study, thirty healthy Hu sheep lambs with similar body weights (17.42 ± 2.02 kg) were randomly selected for the feeding experiment. Lambs were fed diets supplemented with 0.3% Astragalus root powder, and the rumen microbiota density and metabolome were measured to determine the effects of Astragalus on the health of lambs in the rumen. The results showed that the relative abundance of Butyrivibrio fibrisolvens (Bf), Ruminococcus flavefaciens (Rf), Succiniclasticum (Su), and Prevotella (Pr) in the rumen was increased in the Astragalus group (p < 0.01), and metabolic profiling showed that the metabolites, such as L-lyrosine and L-leucine, were upregulated in the Astragalus group (p < 0.01). KEGG functional annotation revealed that upregulated metabolites were mainly enriched in the pathways of amino acid metabolism, lipid metabolism, fatty acid biosynthesis, and bile secretion in the Astragalus group, and downregulated metabolites were enriched in the pathways of methane metabolism and other pathways. Correlation analysis revealed that butyric acid was positively correlated with Roseburia and Blautia (p < 0.05) and negatively correlated with Desulfovibrio (p < 0.05). Thus, by analyzing the interactions of Astragalus root powder with the density of rumen microorganisms and their metabolites in lambs, it was shown that Astragalus root powder could improve the structure of rumen microbiota and their metabolites and then participate in the regulation of amino acid metabolism, lipid metabolism, immune metabolism, and other pathways to improve the efficiency of energy absorption of the lambs.

Metal coordination‐driven assembly of stimulator of interferon genes‐activating nanoparticles for tumor chemo‐immunotherapy

AbstractActivating the stimulator of interferon genes (STING) signaling pathway is critical for enhancing antitumor immunity and remodeling the immunosuppressive tumor microenvironment (TME). Herein, we report the preparation of STING‐activating nanoparticles via metal coordination‐driven assembly of a synthetic STING agonist (i.e., SR717) and a chemotherapeutic drug (i.e., curcumin). After intravenous administration, the assembled nanoparticles could efficiently accumulate in tumors to improve the bioavailability of SR717 and trigger potent STING pathway activation for effective immune responses. Meanwhile, the released curcumin evokes immunogenic cell death in tumors and regulates amino acid metabolism by inhibiting the activation of indoleamine 2,3‐dioxygenase 1, leading to the reversal of the immunosuppressive TME. The antitumor immunity induced by nanoparticles significantly inhibits the growth of primary, recurrent, and metastatic tumors. The assembled nanoparticles are promising for the co‐delivery of STING agonists and drugs in improved tumor chemo‐immunotherapy.

AHL-differential quorum sensing regulation of amino acid metabolism in Hafnia alvei H4.

Quorum sensing (QS) regulation of functional metabolites is rarely reported but a common trait of some bacteria. In this study, we found that QS promoted the extracellular accumulation of glycine and serine while inhibiting the extracellular accumulation of methionine in Hafnia alvei H4. The correlation analysis of five QS signals with the above three QS-regulated amino acids suggested that these QS signals may have functional differences in amino acid regulation. The exogenous AHL add-back studies on genes involved in glycine, serine, and methionine metabolic pathway highlighted that N-octanoyl-l-homoserine lactone (C8-HSL) downregulated the expression of sdhC/fumA genes involved in the succinate to malate pathway, thereby reducing the metabolic flux of the tricarboxylic acid (TCA) cycle as an amino acid metabolism platform. Further in-depth research revealed that the QS system promoted the conversion of folate to tetrahydrofolate (THF) by positively regulating the expression of folA and folM, thus impairing the ability of folate to promote methionine accumulation. Moreover, folate positively regulated the expression of the QS signal synthesis gene luxI, promoting the synthesis of QS signals, which may further enhance the influence of the QS system on amino acid metabolism. These findings contribute to the understanding of amino acid metabolism regulated by QS and provide new perspectives for accurate control of metabolic regulation caused by QS.IMPORTANCEAs one of the important regulatory mechanisms of microorganisms, quorum sensing (QS) is involved in the regulation of various physiological activities. However, few studies on the regulation of amino acid metabolism by QS are available. This study demonstrated that the LuxI-type QS system of Hafnia alvei H4 was involved in the regulation of multiple amino acid metabolism, and different types of QS signals exhibited different roles in regulating amino acid metabolism. Additionally, the regulatory effects of the QS system on amino acid metabolism were investigated from two important cycles that influence the conversion of amino acids, including the TCA cycle and the folate cycle. These findings provide new ideas on the role of QS system in the regulation of amino acid metabolism in organisms.

Metabolic adaptations of Microbacterium sediminis YLB-01 in deep-sea high-pressure environments.

The deep-sea environment is an extremely difficult habitat for microorganisms to survive in due to its intense hydrostatic pressure. However, the mechanisms by which these organisms adapt to such extreme conditions remain poorly understood. In this study, we investigated the metabolic adaptations of Microbacterium sediminis YLB-01, a cold and stress-tolerant microorganism isolated from deep-sea sediments, in response to high-pressure conditions. YLB-01 cells were cultured at normal atmospheric pressure and 28 ℃ until they reached the stationary growth phase. Subsequently, the cells were exposed to either normal pressure or high pressure (30MPa) at 4 ℃ for 7days. Using NMR-based metabolomic and proteomic analyses of YLB-01 cells exposed to high-pressure conditions, we observed significant metabolic changes in several metabolic pathways, including amino acid, carbohydrate, and lipid metabolism. In particular, the high-pressure treatment stimulates cell division and triggers the accumulation of UDP-glucose, a critical factor in cell wall formation. This finding highlights the adaptive strategies used by YLB-01 cells to survive in the challenging high-pressure environments of the deep sea. Specifically, we discovered that YLB-01 cells regulate amino acid metabolism, promote carbohydrate metabolism, enhance cell wall synthesis, and improve cell membrane fluidity in response to high pressure. These adaptive mechanisms play essential roles in supporting the survival and growth of YLB-01 in high-pressure conditions. Our study offers valuable insights into the molecular mechanisms underlying the metabolic adaptation of deep-sea microorganisms to high-pressure environments. KEY POINTS: • NMR-based metabolomic and proteomic analyses were conducted on Microbacterium sediminis YLB-01 to investigate the significant alterations in several metabolic pathways in response to high-pressure treatment. • YLB-01 cells used adaptive strategies (such as regulated amino acid metabolism, promoted carbohydrate metabolism, enhanced cell wall synthesis, and improved cell membrane fluidity) to survive in the challenging high-pressure environment of the deep sea. • High-pressure treatment stimulated cell division and triggered the accumulation of UDP-glucose, a critical factor in cell wall formation, in Microbacterium sediminis YLB-01 cells.

Citrus p-Synephrine Improves Energy Homeostasis by Regulating Amino Acid Metabolism in HFD-Induced Mice.

p-Synephrine is a common alkaloid widely distributed in citrus fruits. However, the effects of p-synephrine on the metabolic profiles of individuals with energy abnormalities are still unclear. In the study, we investigated the effect of p-synephrine on energy homeostasis and metabolic profiles using a high fat diet (HFD)-induced mouse model. We found that p-synephrine inhibited the gain in body weight, liver weight and white adipose tissues weight induced by HFD. p-Synephrine supplementation also reduced levels of serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) but not to a statistically significant degree. Histological analysis showed that HFD induced excessive lipid accumulation and glycogen loss in the liver and adipocyte enlargement in perirenal fat tissue, while p-synephrine supplementation reversed the changes induced by HFD. Moreover, HFD feeding significantly increased mRNA expression levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and reduced the mRNA expression level of interleukin-10 (IL-10) compared to the control group, while p-synephrine supplementation significantly reversed these HFD-induced changes. Liver and serum metabolomic analysis showed that p-synephrine supplementation significantly altered small molecule metabolites in liver and serum in HFD mice and that the changes were closely associated with improvement of energy homeostasis. Notably, amino acid metabolism pathways, both in liver and serum samples, were significantly enriched. Our study suggests that p-synephrine improves energy homeostasis probably by regulating amino acid metabolism in HFD mice, which provides a novel insight into the action mechanism of p-synephrine modulating energy homeostasis.

Holothuria leucospilota polysaccharides (HLP) ameliorate colitis rats via regulation of the metabolic profiling and TLR4/NLRP3 signaling pathways

AbstractRecently, the development of natural polysaccharides for ameliorating immunity and gut metabolism has attracted extensive attention. This study used Holothuria leucospilota polysaccharides (HLP) to explore the improvement mechanism in ulcerative colitis rats on perspectives of immunity and metabolism. The results showed that HLP increased goblet cells’ number and the content of tight junction proteins (zona occludens 1 and occludin) and improved intestinal barrier permeability. The levels of immune cytokines (IL‐4, IL‐6, IL‐10, IL‐18, TNF‐α, and IL‐1β) and the activity of oxidative stress‐related enzymes (superoxide dismutase, catalase, malondialdehyde, and glutathione peroxidase) were regulated. HLP regulated the related genes and proteins expression of immune cytokines, MAPK, and NLRP3 inflammasome. Furthermore, HLP treatment increased the concentration of short‐chain fatty acids (SCFAs) and regulated serum metabolic disorders by regulating amino acid metabolism, SCFA metabolism, and energy metabolism. These results provide a new perspective for developing HLP as a promising functional food for preventing and mitigating colitis.

UPLC-Q-TOF-MS-based metabolomics reveals mechanism of Morinda officinalis iridoid glycosides in treating rheumatoid arthritis and bone loss

This study aimed to investigate the therapeutic effects of Morinda officinalis iridoid glycosides(MOIG) on paw edema and bone loss of rheumatoid arthritis(RA) rats, and analyze its potential mechanism based on ultra-high performance liguid chromatography-guadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS) serum metabolomics. RA rats were established by injecting bovin type Ⅱ collagen. The collagen-induced arthritis(CIA) rats were administered drug by gavage for 8 weeks, the arthritic score were used to evaluate the severity of paw edem, serum bone metabolism biochemical parameters were measured by ELISA kits, Masson staining was used to observe the bone microstructure of the femur in CIA rats. UPLC-Q-TOF-MS was used to analyze the alteration of serum metabolite of CIA rats, principal component analysis(PCA) and partial least squares-discriminant analysis(PLS-DA) were used to screen the potential biomarkers, KEGG database analysis were used to construct related metabolic pathways. The results demonstrated that the arthritic score, serum levels of IL-6 and parameters related with bone metabolism including OCN, CTX-Ⅰ, DPD and TRAP were significantly increased, and the ratio of OPG and RANKL was significantly decreased, the microstructure of bone tissue and cartilage were destructed in CIA rats, while MOIG treatments could significantly reduce arthritis score, mitigate the paw edema, reverse the changes of serum biochemical indicators related with bone metabolism, and improve the microstructure of bone tissue and cartilage of CIA rats. The non-targeted metabolomics results showed that 24 altered metabolites were identified in serum of CIA rats; compared with normal group, 13 significantly altered metabolites related to RA were identified in serum of CIA rats, mainly involving alanine, aspartate and glutamate metabolism; compared with CIA model group, MOIG treatment reversed the alteration of 15 differential metabolites, mainly involving into alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism, valine, leucine and isoleucine biosynthesis. Therefore, MOIG significantly alleviated paw edema, improved the destruction of microstructure of bone and cartilage in CIA rats maybe through involving into the regulation of amino acid metabolism.

Mechanism of simulated lunar dust-induced lung injury in rats based on transcriptomics.

Lunar dust particles are an environmental threat to lunar astronauts, and inhalation of lunar dust can cause lung damage. The current study explored the mechanism of lunar dust simulant (CLDS-i) inducing inflammatory pulmonary injury. Wistar rats were exposed to CLDS-i for 4 h/d and 7d/week for 4 weeks. Pathological results showed that a large number of inflammatory cells gathered and infiltrated in the lung tissues of the simulated lunar dust group, and the alveolar structures were destroyed. Transcriptome analysis confirmed that CLDS-i was mainly involved in the regulation of activation and differentiation of immune inflammatory cells, activated signaling pathways related to inflammatory diseases, and promoted the occurrence and development of inflammatory injury in the lung. Combined with metabolomics analysis, the results of joint analysis of omics were found that the genes Kmo, Kynu, Nos3, Arg1 and Adh7 were involved in the regulation of amino acid metabolism in rat lung tissues, and these genes might be the key targets for the treatment of amino acid metabolic diseases. In addition, the imbalance of amino acid metabolism might be related to the activation of nuclear factor kappaB (NF-κB) signaling pathway. The results of quantitative real-time polymerase chain reaction and Western blot further confirmed that CLDS-i may promote the occurrence and development of lung inflammation and lead to abnormal amino acid metabolism by activating the B cell activation factor (BAFF)/ B cell activation factor receptor (BAFFR)-mediated NF-κB signaling pathway.