scholarly journals Activation of the TCA Cycle to Provide Immune Protection in Zebrafish Immunized by High Magnesium-Prepared Vibrio alginolyticus Vaccine

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun Yang ◽  
Xiao-li Yang ◽  
Yu-bin Su ◽  
Xuan-xian Peng ◽  
Hui Li
Keyword(s):  
Tca Cycle ◽  
Dependent Manner ◽  
High Concentration ◽  
Immune Genes ◽  
Bacterial Diseases ◽  
The Tca Cycle ◽  
Aquaculture Industry ◽  
Innate Immune Genes ◽  
Underlying Mechanisms ◽  
Dose Dependent

Vaccines are safe and efficient in controlling bacterial diseases in the aquaculture industry and are in line with green farming. The present study develops a previously unreported approach to prepare a live-attenuated V. alginolyticus vaccine by culturing bacteria in a high concentration of magnesium to attenuate bacterial virulence. Furthermore, metabolomes of zebrafish immunized with the live-attenuated vaccines were compared with those of survival and dying zebrafish infected by V. alginolyticus. The enhanced TCA cycle and increased fumarate were identified as the most key metabolic pathways and the crucial biomarker of vaccine-mediated and survival fish, respectively. Exogenous fumarate promoted expression of il1β, il8, il21, nf-κb, and lysozyme in a dose-dependent manner. Among the five innate immune genes, the elevated il1β, il8, and lysozyme are overlapped in the vaccine-immunized zebrafish and the survival from the infection. These findings highlight a way in development of vaccines and exploration of the underlying mechanisms.

scholarly journals Metabonomic approaches investigate diosbulbin B-induced pulmonary toxicity and elucidate its underling mechanism in male mice

2021 ◽  
Vol 10 (2) ◽  
pp. 272-276
Author(s):  
Hainan Ji ◽  
Chang Liu ◽  
Na Tong ◽  
Naining Song ◽  
Baoliang Xu ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Tca Cycle ◽  
Lung Toxicity ◽  
Mouse Lung ◽  
Lung Cells ◽  
Dependent Manner ◽  
The Tca Cycle ◽  
Atp Supply ◽  
Endogenous Metabolites ◽  
Dose Dependent

Abstract Air Potato Yam is widely used in the treatment of many conditions such as cancer, inflammation, and goiter. Diosbulbin B (DIOB) is the primary active component of Air Potato Yam, and it exhibits anti-tumor and anti-inflammatory properties. The main purpose of this study was to determine the mechanism by which DIOB induces lung toxicity, using metabonomics and molecular biology techniques. The results showed that the lung toxicity induced by DIOB may occur because of a DIOB-induced increase in the plasma levels of long-chain free fatty acids and endogenous metabolites related to inflammation. In addition, treatment with DIOB increases the expression of the cyp3a13 enzyme, which leads to enhanced toxicity in a dose-dependent manner. The molecular mechanism underlying toxicity in mouse lung cells is the DIOB-mediated inhibition of fatty acid β-oxidation, partial glycolysis, and the TCA cycle, but DIOB treatment can also compensate for the low Adenosine triphosphate (ATP) supply levels by improving the efficiency of the last step of the glycolysis reaction and by increasing the rate of anaerobic glycolysis. Using metabonomics and other methods, we identified the toxic effects of DIOB on the lung and clarified the underlying molecular mechanism.

scholarly journals Succinate Promotes Phagocytosis of Monocytes/Macrophages in Teleost Fish

2021 ◽  
Vol 8 ◽  
Author(s):  
Dai-xiao Yang ◽  
Hao Yang ◽  
Yun-chao Cao ◽  
Ming Jiang ◽  
Jun Zheng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Tca Cycle ◽  
Edwardsiella Tarda ◽  
Resistant Bacteria ◽  
Dependent Manner ◽  
Antibiotic Resistant ◽  
Expression Of Genes ◽  
The Tca Cycle ◽  
Before And After ◽  
Dose Dependent

Development of immunity-based strategy to manage bacterial infection is urgently needed in aquaculture due to the widespread of antibiotic-resistant bacteria. Phagocytosis serves as the first line defense in innate immunity that engulfs bacteria and restricts their proliferations and invasions. However, the mechanism underlying the regulation of phagocytosis is not fully elucidated and the way to boost phagocytosis is not yet explored. In this manuscript, we profiled the metabolomes of monocytes/macrophages isolated from Nile tilapia, prior and after phagocytosis on Vibrio alginolyticus. Monocytes/macrophages showed a metabolic shift following phagocytosis. Interestingly, succinate was accumulated after phagocytosis and was identified as a crucial biomarker to distinguish before and after phagocytosis. Exogenous succinate increased the phagocytotic rate of monocytes/macrophages in a dose-dependent manner. This effect was dependent on the TCA cycle as the inhibitor of malonate that targets succinate dehydrogenase abrogated the effect. Meanwhile, exogenous succinate regulated the expression of genes associated with innate immune and phagocytosis. In addition, succinate-potentiated phagocytosis was applicable to both gram-negative and -positive cells, including V. alginolyticus, Edwardsiella tarda, Streptococcus agalactiae, and Streptococcus iniae. Our study shed light on the understanding of how modulation on host’s metabolism regulates immune response, and this can be a potent therapeutic approach to control bacterial infections in aquaculture.

Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

2019 ◽  
Vol 18 (1) ◽  
pp. 34-38
Author(s):  
Chen Lei ◽  
Pan Xiang ◽  
Shen Yonggang ◽  
Song Kai ◽  
Zhong Xingguo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guinea Pig ◽  
Smooth Muscles ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

scholarly journals Metabolomics of aging in primary fibroblasts from small and large breed dogs

GeroScience ◽  
2021 ◽  
Author(s):  
Paul S. Brookes ◽  
Ana Gabriela Jimenez
Keyword(s):  
Aging Process ◽  
Tca Cycle ◽  
Therapeutic Strategies ◽  
Targeted Metabolomics ◽  
The Tca Cycle ◽  
Age Dependent ◽  
Primary Fibroblasts ◽  
Aging Rates ◽  
Underlying Mechanisms ◽  
Coenzyme A Biosynthesis

AbstractAmong several animal groups (eutherian mammals, birds, reptiles), lifespan positively correlates with body mass over several orders of magnitude. Contradicting this pattern are domesticated dogs, with small dog breeds exhibiting significantly longer lifespans than large dog breeds. The underlying mechanisms of differing aging rates across body masses are unclear, but it is generally agreed that metabolism is a significant regulator of the aging process. Herein, we performed a targeted metabolomics analysis on primary fibroblasts isolated from small and large breed young and old dogs. Regardless of size, older dogs exhibited lower glutathione and ATP, consistent with a role for oxidative stress and bioenergetic decline in aging. Furthermore, several size-specific metabolic patterns were observed with aging, including the following: (i) An apparent defect in the lower half of glycolysis in large old dogs at the level of pyruvate kinase. (ii) Increased glutamine anaplerosis into the TCA cycle in large old dogs. (iii) A potential defect in coenzyme A biosynthesis in large old dogs. (iv) Low nucleotide levels in small young dogs that corrected with age. (v) An age-dependent increase in carnitine in small dogs that was absent in large dogs. Overall, these data support the hypothesis that alterations in metabolism may underlie the different lifespans of small vs. large breed dogs, and further work in this area may afford potential therapeutic strategies to improve the lifespan of large dogs.

scholarly journals Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner

2020 ◽  
Vol 13 (10) ◽  
pp. dmm047134
Author(s):  
Leonie Drews ◽  
Marcel Zimmermann ◽  
Philipp Westhoff ◽  
Dominik Brilhaus ◽  
Rebecca E. Poss ◽  
...  
Keyword(s):  
Amino Acids ◽  
Energy Metabolism ◽  
Glutamate Dehydrogenase ◽  
Mitochondrial Respiration ◽  
Tca Cycle ◽  
Dependent Manner ◽  
Independent Manner ◽  
The Tca Cycle ◽  
Branched Chain ◽  
Tca Cycle Intermediates

ABSTRACTAstrocyte dysfunction is a primary factor in hepatic encephalopathy (HE) impairing neuronal activity under hyperammonemia. In particular, the early events causing ammonia-induced toxicity to astrocytes are not well understood. Using established cellular HE models, we show that mitochondria rapidly undergo fragmentation in a reversible manner upon hyperammonemia. Further, in our analyses, within a timescale of minutes, mitochondrial respiration and glycolysis were hampered, which occurred in a pH-independent manner. Using metabolomics, an accumulation of glucose and numerous amino acids, including branched chain amino acids, was observed. Metabolomic tracking of 15N-labeled ammonia showed rapid incorporation of 15N into glutamate and glutamate-derived amino acids. Downregulating human GLUD2 [encoding mitochondrial glutamate dehydrogenase 2 (GDH2)], inhibiting GDH2 activity by SIRT4 overexpression, and supplementing cells with glutamate or glutamine alleviated ammonia-induced inhibition of mitochondrial respiration. Metabolomic tracking of 13C-glutamine showed that hyperammonemia can inhibit anaplerosis of tricarboxylic acid (TCA) cycle intermediates. Contrary to its classical anaplerotic role, we show that, under hyperammonemia, GDH2 catalyzes the removal of ammonia by reductive amination of α-ketoglutarate, which efficiently and rapidly inhibits the TCA cycle. Overall, we propose a critical GDH2-dependent mechanism in HE models that helps to remove ammonia, but also impairs energy metabolism in mitochondria rapidly.

scholarly journals Emodin promotes apoptosis of human endometrial cancer through regulating the MAPK and PI3K/ AKT pathways

2019 ◽  
Vol 13 (1) ◽  
pp. 489-496 ◽  
Author(s):  
Jun Jiang ◽  
Nanyang Zhou ◽  
Pian Ying ◽  
Ting Zhang ◽  
Ruojia Liang ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Signaling Pathways ◽  
Tumor Development ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Western Blot Assay ◽  
Anti Oxidant ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Dose Dependent

AbstractEmodin, a major component of rhubarb, has anti-tumor effects in a variety of cancers, influencing multiple steps of tumor development through modulating several signaling pathways. The aim of this study is to examine the effect of emodin on cell apoptosis and explore the underlying mechanisms in human endometrial cancer cells. Here we report that emodin can inhibit KLE cell proliferation and induce apoptosis in a time- and dose-dependent manner. Western blot assay found that emodin was involved in MAPK and PI3K/Akt signaling pathways. Specifically, emodin significantly suppressed the phosphorylation of AKT, and enhanced the phosphorylation of MAPK pathways. Furthermore, the generation of reactive oxygen species (ROS) was up-regulated in KLE cells upon treatment with emodin, while the anti-oxidant agent N-acetyl cysteine (NAC) can inhibit emodin-induced apoptosis and promote the activation of AKT and Bcl-2. Taken together, we revealed that emodin may induce apoptosis in KLE cells through regulating the PI3K/AKT and MAPK signaling pathways, indicating the importance of emodin as an anti-tumor agent.

scholarly journals Triterpenoid Saponin AG8 from Ardisia gigantifolia stapf. Induces Triple Negative Breast Cancer Cells Apoptosis through Oxidative Stress Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Li-Hua Mu ◽  
Li-Hua Wang ◽  
Teng-Fei Yu ◽  
Yu-Ning Wang ◽  
Hong Yan ◽  
...  
Keyword(s):  
Triple Negative ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Ros Generation ◽  
Triterpenoid Saponin ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Underlying Mechanisms ◽  
Apoptotic Pathways ◽  
Dose Dependent

Triple-negative breast cancers (TNBCs) are associated with poor patient survival because of the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expressions. Our previous studies have shown that the triterpenoid saponin AG8 from Ardisia gigantifolia stapf. inhibits the proliferation of MDA-MB-231 cells. In this study, the effects of AG8 were further analyzed in different TNBC cell types: MDA-MB-231, BT-549, and MDA-MB-157 cells. AG8 inhibited the viability of MDA-MB-231, BT-549, and MDA-MB-157 cells in a dose-dependent manner and showed stronger cytotoxicity to African American (AA) and mesenchymal (M) subtypes than Caucasian (CA) and mesenchymal stem-like (MSL) subtypes, respectively. AG8 impaired the uptake of MitoTracker Red CMXRos by the mitochondria of TNBC cells in a dose-dependent manner, and this was recovered by N-acetyl-l-cysteine (NAC). AG8 affected GSH, SOD, and MDA levels of TNBC cells, but different TNBC subtypes had different sensitivities to AG8 and NAC. In addition, we found that AG8 increased the Bax/Bcl-2 ratio and the levels of cytoplasmic cytochrome c and significantly decreased phosphorylation of ERK and AKT in BT549 and MDA-MB-157 cells. AG8 elicited its anticancer effects through ROS generation, ERK and AKT activation, and by triggering mitochondrial apoptotic pathways in TNBC cells. AG8 had selective cytotoxic effects against the AA and M TNBC subtypes and markedly induced MDA-MB-157 (AA subtype) cell apoptosis through pathways that were not associated with ROS, which was different from the other two subtypes. The underlying mechanisms should be further investigated.

scholarly journals Effects of cGMP and sodium nitroprusside on odor responses in turtle olfactory sensory neurons

1998 ◽  
Vol 275 (5) ◽  
pp. C1201-C1206 ◽  
Author(s):  
Kouhei Inamura ◽  
Makoto Kashiwayanagi ◽  
Kenzo Kurihara
Keyword(s):  
Sodium Nitroprusside ◽  
Dependent Manner ◽  
High Concentration ◽  
No Donor ◽  
Inward Current ◽  
Inward Currents ◽  
Induced Currents ◽  
Dose Dependent ◽  
Camp And Cgmp ◽  
Dependent Pathway

The effects of cGMP and sodium nitroprusside (SNP) on odor responses in isolated turtle olfactory neurons were examined. The inward current induced by dialysis of a mixture of 1 mM cAMP and 1 mM cGMP was similar to that induced by dialysis of 1 mM cAMP or 1 mM cGMP alone. After the neurons were desensitized by the application of 1 mM cGMP, 3 mM 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, did not elicit any current, indicating that both cAMP and cGMP activated the same channel. Extracellular application of SNP, a nitric oxide (NO) donor, evoked inward currents in a dose-dependent manner. However, application of SNP did not induce any currents after desensitization of the cGMP-induced currents, suggesting that SNP-induced currents are mediated via the cGMP-dependent pathway. Application of the cAMP-producing odorants to the neurons induced a large inward current even after neurons were desensitized to a high concentration of cGMP or SNP. These results suggest that the transduction pathway independent of cAMP, cGMP, and NO also contributes to the generation of odor responses in addition to the cAMP-dependent pathway.

Inhibitory effect of neuropeptide Y on adrenergic and cholinergic transmission in rat urinary bladder and urethra

1994 ◽  
Vol 266 (4) ◽  
pp. R1411-R1417 ◽  
Author(s):  
L. V. Tran ◽  
G. T. Somogyi ◽  
W. C. De Groat
Keyword(s):  
Urinary Tract ◽  
Neuropeptide Y ◽  
Lower Urinary Tract ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Ach Release ◽  
High Concentration ◽  
Rat Urinary Bladder ◽  
Dose Dependent ◽  
Lower Urinary

The effects of porcine neuropeptide Y (NPY) on electrically evoked release of [3H]norepinephrine ([3H]NE) and [3H]acetylcholine ([3H]ACh) were investigated in isolated preparations of the rat lower urinary tract. In the urethra, NPY (0.02-0.5 microM) decreased the release of [3H]NE in a dose-dependent manner (10-53%). In the bladder base the inhibitory effect of NPY on [3H]NE release was not dose dependent. A low concentration (0.1 microM) decreased the release (38%), whereas a high concentration (0.5 microM) had no effect. However, in atropine-treated preparations, 0.5 microM NPY elicited a significant inhibition (43%). These observations suggest that 0.5 microM NPY elicits two opposing actions: a direct inhibitory action on adrenergic terminals and an indirect disinhibitory action to eliminate heterosynaptic cholinergic inhibition of [3H]NE release. In both tissues the action of NPY on [3H]NE release was not significantly modified by the alpha-adrenergic blocking agent yohimbine (1 microM). [3H]ACh release in the bladder body was not altered by 0.1 microM NPY but was suppressed (39%) by 1 microM NPY. The effect of NPY (1 microM) on [3H]ACh release was dependent on the frequency of stimulation. NPY suppressed the release at 2-Hz stimulation but had no significant effect at 20 Hz. These results suggest that NPY may have an important role in the neural regulation of the lower urinary tract by exerting differential effects on the release of cholinergic and adrenergic transmitters via autoinhibition and heterosynaptic interactions.

scholarly journals ROS-Induced GATA4 and GATA6 Downregulation Inhibits StAR Expression in LPS-Treated Porcine Granulosa-Lutein Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Xiaolu Qu ◽  
Leyan Yan ◽  
Rihong Guo ◽  
Hui Li ◽  
Zhendan Shi
Keyword(s):  
Molecular Mechanisms ◽  
Cell Model ◽  
Animal Husbandry ◽  
Dependent Manner ◽  
Progesterone Production ◽  
Progesterone Synthesis ◽  
Porcine Granulosa Cell ◽  
Underlying Mechanisms ◽  
Dose Dependent

LPS is a major endotoxin produced by gram-negative bacteria, and exposure to it commonly occurs in animal husbandry. Previous studies have shown that LPS infection disturbs steroidogenesis, including progesterone production, and subsequently decreases animal reproductive performance. However, little information about the underlying mechanisms is available thus far. In the present study, an in vitro-luteinized porcine granulosa cell model was used to study the underlying molecular mechanisms of LPS treatment. We found that LPS significantly inhibits progesterone production and downregulates the expressions of progesterone synthesis-associated genes (StAR, CYP11A1, and 3β-HSD). Furthermore, the levels of ROS were significantly increased in an LPS dose-dependent manner. Moreover, transcriptional factors GATA4 and GATA6, but not NR5A1, were significantly downregulated. Elimination of LPS-stimulated ROS by melatonin or vitamin C could restore the expressions of GATA4, GATA6, and StAR. In parallel, StAR expression was also inhibited by the knockdown of GATA4 and GATA6. Based on these data, we conclude that LPS impairs StAR expression via the ROS-induced downregulation of GATA4 and GATA6. Collectively, these findings provide new insights into the understanding of reproductive losses in animals suffering from bacterial infection and LPS exposure.

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